216 results on '"Krit1"'
Search Results
2. Inhibition of the HEG1–KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells
- Author
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Lopez‐Ramirez, Miguel Alejandro, McCurdy, Sara, Li, Wenqing, Haynes, Mark K, Hale, Preston, Francisco, Karol, Oukoloff, Killian, Bautista, Matthew, Choi, Chelsea HJ, Sun, Hao, Gongol, Brendan, Shyy, John Y, Ballatore, Carlo, Sklar, Larry A, and Gingras, Alexandre R
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,1.1 Normal biological development and functioning ,Underpinning research ,Cardiovascular ,endothelial cells ,HEG1 ,KLF2 ,KLF4 ,KRIT1 ,Biological sciences - Abstract
The transmembrane protein heart of glass1 (HEG1) directly binds to and recruits Krev interaction trapped protein 1 (KRIT1) to endothelial junctions to form the HEG1-KRIT1 protein complex that establishes and maintains junctional integrity. Genetic inactivation or knockdown of endothelial HEG1 or KRIT1 leads to the upregulation of transcription factors Krüppel-like factors 4 and 2 (KLF4 and KLF2), which are implicated in endothelial vascular homeostasis; however, the effect of acute inhibition of the HEG1-KRIT1 interaction remains incompletely understood. Here, we report a high-throughput screening assay and molecular design of a small-molecule HEG1-KRIT1 inhibitor to uncover acute changes in signaling pathways downstream of the HEG1-KRIT1 protein complex disruption. The small-molecule HEG1-KRIT1 inhibitor 2 (HKi2) was demonstrated to be a bona fide inhibitor of the interaction between HEG1 and KRIT1 proteins, by competing orthosterically with HEG1 through covalent reversible interactions with the FERM (4.1, ezrin, radixin, and moesin) domain of KRIT1. The crystal structure of HKi2 bound to KRIT1 FERM revealed that it occupies the same binding pocket on KRIT1 as the HEG1 cytoplasmic tail. In human endothelial cells (ECs), acute inhibition of the HEG1-KRIT1 interaction by HKi2 increased KLF4 and KLF2 mRNA and protein levels, whereas a structurally similar inactive compound failed to do so. In zebrafish, HKi2 induced expression of klf2a in arterial and venous endothelium. Furthermore, genome-wide RNA transcriptome analysis of HKi2-treated ECs under static conditions revealed that, in addition to elevating KLF4 and KLF2 expression, inhibition of the HEG1-KRIT1 interaction mimics many of the transcriptional effects of laminar blood flow. Furthermore, HKi2-treated ECs also triggered Akt signaling in a phosphoinositide 3-kinase (PI3K)-dependent manner, as blocking PI3K activity blunted the Akt phosphorylation induced by HKi2. Finally, using an in vitro colocalization assay, we show that HKi6, an improved derivative of HKi2 with higher affinity for KRIT1, significantly impedes recruitment of KRIT1 to mitochondria-localized HEG1 in CHO cells, indicating a direct inhibition of the HEG1-KRIT1 interaction. Thus, our results demonstrate that early events of the acute inhibition of HEG1-KRIT1 interaction with HKi small-molecule inhibitors lead to: (i) elevated KLF4 and KLF2 gene expression; and (ii) increased Akt phosphorylation. Thus, HKi's provide new pharmacologic tools to study acute inhibition of the HEG1-KRIT1 protein complex and may provide insights to dissect early signaling events that regulate vascular homeostasis.
- Published
- 2021
3. Case Report: A novel heterozygous nonsense mutation in KRIT1 cause hereditary cerebral cavernous malformation.
- Author
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Zhenxing Liu, Kaikai Guo, Xuebin Hu, and Xianqin Zhang
- Subjects
NONSENSE mutation ,CAVERNOUS hemangioma ,HUMAN abnormalities ,CENTRAL nervous system ,GENETIC disorder diagnosis - Abstract
Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system and mainly characterized by enlarged capillary cavities without intervening brain parenchyma. Genetic studies have identified three diseasecausing genes (CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10) responsible for CCM. Here, we characterized a four-generation family diagnosed with CCM and identified a novel heterozygous mutation c.1159C>T, p.Q387X in KRIT1 gene by whole exome sequencing and Sanger sequencing. The Q387X mutation resulted in premature termination of KRIT1 protein, which was predicted to be deleterious by the ACMG/AMP 2015 guideline. Our results provide novel genetic evidence support that KRIT1 mutations cause CCM, and are helpful to the treatment and genetic diagnosis of CCM. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. A novel KRIT1/CCM1 mutation accompanied by a NOTCH3 mutation in a Chinese family with multiple cerebral cavernous malformations.
- Author
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Li, Chunwang, Liu, Penghui, Huang, Weilin, Wang, Haojie, Ma, Ke, Zhuo, Lingyun, Kang, Yaqing, He, Qiu, Lin, Yuanxiang, Kang, Dezhi, and Lin, Fuxin
- Subjects
GENETIC mutation ,CEREBRAL hemorrhage ,EPILEPSY ,INTRACRANIAL hemorrhage ,INTRACEREBRAL hematoma ,MISSENSE mutation - Abstract
Family cerebral cavernous malformations (FCCMs) are mainly inherited through the mutation of classical CCM genes, including CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. FCCMs can cause severe clinical symptoms, including epileptic seizures, intracranial hemorrhage (ICH), or functional neurological deficits (FNDs). In this study, we reported a novel mutation in KRIT1 accompanied by a NOTCH3 mutation in a Chinese family. This family consists of 8 members, 4 of whom had been diagnosed with CCMs using cerebral MRI (T1WI, T2WI, SWI). The proband (II-2) and her daughter (III-4) had intracerebral hemorrhage and refractory epilepsy, respectively. Based on whole-exome sequencing (WES) data and bioinformatics analysis from 4 patients with multiple CCMs and 2 normal first-degree relatives, a novel KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in intron 13 was considered a pathogenic gene in this family. Furthermore, based on 2 severe and 2 mild CCM patients, we found an SNV missense mutation, NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C), in NOTCH3. Finally, the KRIT1 and NOTCH3 mutations were validated in 8 members using Sanger sequencing. This study revealed a novel KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in a Chinese CCM family, which had not been reported previously. Moreover, the NOTCH3 mutation NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C) might be a second hit and associated with the progression of CCM lesions and severe clinical symptoms. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. KRIT1: A Traffic Warden at the Busy Crossroads Between Redox Signaling and the Pathogenesis of Cerebral Cavernous Malformation Disease.
- Author
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Perrelli, Andrea, Ferraris, Chiara, Berni, Elisa, Glading, Angela J., and Retta, Saverio Francesco
- Subjects
- *
CELL adhesion , *HOMEOSTASIS , *OXIDATION-reduction reaction , *ADHERENS junctions , *TISSUE adhesions , *HUMAN abnormalities , *SCAFFOLD proteins , *OXIDATIVE stress - Abstract
Significance: KRIT1 (Krev interaction trapped 1) is a scaffolding protein that plays a critical role in vascular morphogenesis and homeostasis. Its loss-of-function has been unequivocally associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease of genetic origin characterized by defective endothelial cell–cell adhesion and ensuing structural alterations and hyperpermeability in brain capillaries. KRIT1 contributes to the maintenance of endothelial barrier function by stabilizing the integrity of adherens junctions and inhibiting the formation of actin stress fibers. Recent Advances: Among the multiple regulatory mechanisms proposed so far, significant evidence accumulated over the past decade has clearly shown that the role of KRIT1 in the stability of endothelial barriers, including the blood-brain barrier, is largely based on its involvement in the complex machinery governing cellular redox homeostasis and responses to oxidative stress and inflammation. KRIT1 loss-of-function has, indeed, been demonstrated to cause an impairment of major redox-sensitive mechanisms involved in spatiotemporal regulation of cell adhesion and signaling, which ultimately leads to decreased cell–cell junction stability and enhanced sensitivity to oxidative stress and inflammation. Critical Issues: This review explores the redox mechanisms that influence endothelial cell adhesion and barrier function, focusing on the role of KRIT1 in such mechanisms. We propose that this supports a novel model wherein redox signaling forms the common link between the various pathogenetic mechanisms and therapeutic approaches hitherto associated with CCM disease. Future Directions: A comprehensive characterization of the role of KRIT1 in redox control of endothelial barrier physiology and defense against oxy-inflammatory insults will provide valuable insights into the development of precision medicine strategies. Antioxid. Redox Signal. 38, 496–528. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models.
- Author
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Phillips, Chelsea M., Stamatovic, Svetlana M., Keep, Richard F., and Andjelkovic, Anuska V.
- Subjects
- *
ANIMAL models in research , *MOLECULAR pathology , *PATHOLOGY , *HUMAN abnormalities , *HEMORRHAGIC stroke , *PATHOGENESIS - Abstract
Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell–cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
7. Inhibition of the HEG1–KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells
- Author
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Miguel Alejandro Lopez‐Ramirez, Sara McCurdy, Wenqing Li, Mark K. Haynes, Preston Hale, Karol Francisco, Killian Oukoloff, Matthew Bautista, Chelsea H.J. Choi, Hao Sun, Brendan Gongol, John Y. Shyy, Carlo Ballatore, Larry A. Sklar, and Alexandre R. Gingras
- Subjects
endothelial cells ,HEG1 ,KLF2 ,KLF4 ,KRIT1 ,Biology (General) ,QH301-705.5 - Abstract
ABSTRACT The transmembrane protein heart of glass1 (HEG1) directly binds to and recruits Krev interaction trapped protein 1 (KRIT1) to endothelial junctions to form the HEG1–KRIT1 protein complex that establishes and maintains junctional integrity. Genetic inactivation or knockdown of endothelial HEG1 or KRIT1 leads to the upregulation of transcription factors Krüppel‐like factors 4 and 2 (KLF4 and KLF2), which are implicated in endothelial vascular homeostasis; however, the effect of acute inhibition of the HEG1–KRIT1 interaction remains incompletely understood. Here, we report a high‐throughput screening assay and molecular design of a small‐molecule HEG1–KRIT1 inhibitor to uncover acute changes in signaling pathways downstream of the HEG1–KRIT1 protein complex disruption. The small‐molecule HEG1–KRIT1 inhibitor 2 (HKi2) was demonstrated to be a bona fide inhibitor of the interaction between HEG1 and KRIT1 proteins, by competing orthosterically with HEG1 through covalent reversible interactions with the FERM (4.1, ezrin, radixin, and moesin) domain of KRIT1. The crystal structure of HKi2 bound to KRIT1 FERM revealed that it occupies the same binding pocket on KRIT1 as the HEG1 cytoplasmic tail. In human endothelial cells (ECs), acute inhibition of the HEG1–KRIT1 interaction by HKi2 increased KLF4 and KLF2 mRNA and protein levels, whereas a structurally similar inactive compound failed to do so. In zebrafish, HKi2 induced expression of klf2a in arterial and venous endothelium. Furthermore, genome‐wide RNA transcriptome analysis of HKi2‐treated ECs under static conditions revealed that, in addition to elevating KLF4 and KLF2 expression, inhibition of the HEG1–KRIT1 interaction mimics many of the transcriptional effects of laminar blood flow. Furthermore, HKi2‐treated ECs also triggered Akt signaling in a phosphoinositide 3‐kinase (PI3K)‐dependent manner, as blocking PI3K activity blunted the Akt phosphorylation induced by HKi2. Finally, using an in vitro colocalization assay, we show that HKi6, an improved derivative of HKi2 with higher affinity for KRIT1, significantly impedes recruitment of KRIT1 to mitochondria‐localized HEG1 in CHO cells, indicating a direct inhibition of the HEG1–KRIT1 interaction. Thus, our results demonstrate that early events of the acute inhibition of HEG1–KRIT1 interaction with HKi small‐molecule inhibitors lead to: (i) elevated KLF4 and KLF2 gene expression; and (ii) increased Akt phosphorylation. Thus, HKi’s provide new pharmacologic tools to study acute inhibition of the HEG1–KRIT1 protein complex and may provide insights to dissect early signaling events that regulate vascular homeostasis.
- Published
- 2021
- Full Text
- View/download PDF
8. KRIT1‐positive hyperkeratotic cutaneous capillary venous malformation.
- Author
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Matarneh, Bayan, Cottrell, Catherine E., Choi, Samantha, Pearson, Gregory, Fung, Bonita, Koo, Selene C., Lillis, Anna P., Ho, Mai‐Lan, and Fernandez Faith, Esteban
- Subjects
- *
HUMAN abnormalities , *CAPILLARIES , *CUTANEOUS manifestations of general diseases , *IMMUNOSTAINING , *HISTOPATHOLOGY - Abstract
Cerebral cavernous malformations (CCM) may present in sporadic or familial forms, with different cutaneous manifestations including deep blue nodules, capillary malformations, and hyperkeratotic cutaneous capillary venous malformations (HCCVM). We report the case of an infant with a KRIT1‐positive HCCVM associated with familial CCM. Moreover, histopathology showed positive immunohistochemical stain with GLUT1, further expanding the differential diagnosis of GLUT1‐positive vascular anomalies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
9. Mesenteric cysts, lymphatic leak, and cerebral cavernous malformation in a proband with KRIT1‐related disease.
- Author
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Moller‐Hansen, Ashley, Huynh, Stephanie, Boerkoel, Cornelius F., and Chin, Hui‐Lin
- Abstract
Cerebral cavernous malformations (CCMs) of the central nervous system arise sporadically or secondary to genomic variation. Established genetic etiologies include deleterious variants in KRIT1 (CCM1), malcavernin (CCM2), and PDCD10 (CCM3). KRIT1‐related disease has not been described in conjunction with lymphatic defects, although lymphatic defects with abnormal endothelial cell junctions have been observed in mice deficient in HEG1‐KRIT1 signaling. We report a proband with CCMs, multiple chylous mesenteric cysts, and chylous ascites with leaky lymphatic vasculature. Clinical short‐read exome sequencing detected a disease‐associated KRIT1 variant (NM_194456.1:c.[1927C>T];[=], p.(Gln643*)). We postulate an expansion of KRIT1‐related disease to include lymphatic malformations and lymphatic endothelial dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
10. The frameshift Leu220Phefs*2 variant in KRIT1 accounts for early acute bleeding in patients affected by cerebral cavernous malformation
- Author
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Autilia Tommasina Buonagura, Teresa Somma, Francesca Vitulli, Giuseppina Vitiello, Immacolata Andolfo, Felice Esposito, Roberta Russo, Achille Iolascon, and Paolo Cappabianca
- Subjects
Cerebral cavernous malformation ,KRIT1 ,Genetic counseling ,Genetic testing ,Next-generation sequencing ,Surgery ,RD1-811 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background and Objectives: Cerebral cavernous malformation (CCM) is a neurovascular disease characterized by abnormally expanded and tortuous microvessels with increased predisposition to thrombosis and focal hemorrhage. Its incidence is estimated to range between 0.4% and 0.8%. Sporadic and familial forms of CCM are described. The first one is characterized by single lesion, while the familial form is defined by multiple malformations. In this scenario, more than 300 mutations affecting the CCM genes have been described to date, but the exact pathogenic mechanism is yet unknown. Most of the causative variants of KRIT1 gene are frameshift but there are many missense and nonsense variants and they have been found some splicing mutations. The diagnosis is based on magnetic resonance images (MRI) and genetic testing. Case report: A 15-year-old male presented with a two weeks duration worsening headache accompanied by vomiting and three months behavioral changes. Computer tomography revealed a large right temporal lesion with other smaller in left parietal and left cerebellar region. At the time of diagnosis, the two siblings of the proband were asymptomatic. Nevertheless, four months later, the 7-years-old brother was admitted to the emergency room for balance deficit, diplopia, right-hitting nystagmus and stiff neck with deviation of the head. A cerebral CT revealed polylobate hyperdense mass of the middle cerebral pedicle associated to acute bleeding. A genetic testing for hereditary cavernous brain malformation was carried out. Results: The molecular analysis identified a 2-bp duplication (NM_194456.1:c.658_659dupTT) as heterozygous within the exon 8 of CCM1/KRIT1 gene (Fig. 1C). This duplication leads to a frameshift variant, resulting in a premature stop codon (p.Leu220Phefs*2). Discussion: The clinical data collected confirm the variable phenotypic expression of CCM and suggest a greater severity of symptoms in the youngest patients.
- Published
- 2021
- Full Text
- View/download PDF
11. KRIT1 in vascular biology and beyond.
- Author
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Glading AJ
- Subjects
- Humans, Animals, Apoptosis Regulatory Proteins metabolism, Apoptosis Regulatory Proteins genetics, Mutation, KRIT1 Protein metabolism, KRIT1 Protein genetics, Hemangioma, Cavernous, Central Nervous System metabolism, Hemangioma, Cavernous, Central Nervous System genetics, Hemangioma, Cavernous, Central Nervous System pathology, Endothelial Cells metabolism, Endothelial Cells pathology
- Abstract
KRIT1 is a 75 kDa scaffolding protein which regulates endothelial cell phenotype by limiting the response to inflammatory stimuli and maintaining a quiescent and stable endothelial barrier. Loss-of-function mutations in KRIT1 lead to the development of cerebral cavernous malformations (CCM), a disease marked by the formation of abnormal blood vessels which exhibit a loss of barrier function, increased endothelial proliferation, and altered gene expression. While many advances have been made in our understanding of how KRIT1, and the functionally related proteins CCM2 and PDCD10, contribute to the regulation of blood vessels and the vascular barrier, some important open questions remain. In addition, KRIT1 is widely expressed and KRIT1 and the other CCM proteins have been shown to play important roles in non-endothelial cell types and tissues, which may or may not be related to their role as pathogenic originators of CCM. In this review, we discuss some of the unsettled questions regarding the role of KRIT1 in vascular physiology and discuss recent advances that suggest this ubiquitously expressed protein may have a role beyond the endothelial cell., (© 2024 The Author(s).)
- Published
- 2024
- Full Text
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12. Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants.
- Author
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Fusco, Carmela, Nardella, Grazia, Petracca, Antonio, Ronchi, Dario, Paciello, Nicola, Di Giacomo, Marilena, Gambardella, Stefano, Lanfranconi, Silvia, Zampatti, Stefania, D'Agruma, Leonardo, Micale, Lucia, and Castori, Marco
- Subjects
- *
C-terminal residues , *CENTRAL nervous system , *HUMAN genetic variation - Abstract
Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system which may occur sporadically or segregate within families due to heterozygous variants in KRIT1/CCM1, MGC4607/CCM2 or PDCD10/CCM3. Intronic variants are not uncommon in familial CCM, but their clinical interpretation is often hampered by insufficient data supporting in silico predictions. Here, the mRNA analysis for two intronic unpublished variants (KRIT1 c.1147‐7 T > G and PDCD10 c.395 + 2 T > G) and three previously published variants in KRIT1 but without data supporting their effects was carried out. This study demonstrated that all variants can induce a frameshift with the lack of residues located in the C‐terminal regions and involved in protein–protein complex formation, which is essential for vascular homeostasis. These results support the introduction of mRNA analysis in the diagnostic pathway of familial CCM and expand the knowledge of abnormal splicing patterning in this disorder. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
13. Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models
- Author
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Chelsea M. Phillips, Svetlana M. Stamatovic, Richard F. Keep, and Anuska V. Andjelkovic
- Subjects
cerebrovascular malformation ,KRIT1 ,CCM2 ,PDCD10 ,hemorrhagic lesions ,CCM animal models ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell–cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics.
- Published
- 2022
- Full Text
- View/download PDF
14. Myoclonus-Dystonia Plus Syndrome With Early-Onset Multiple Cerebral Cavernous Malformation Type 1 and Growth Hormone Deficiency Associated With Novel 7q21.13-q21.3 Deletion: A Pediatric Case Report.
- Author
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Matsubara K, Kuki I, Yamada Y, Mori J, and Okazaki S
- Abstract
Myoclonus-dystonia syndrome (MDS) presents with both rapid myoclonus and dystonia, which is caused by mutations in the sarcoglycan (SGCE) gene. However, its complications and management remain unclear. Here, we report a case involving a girl with MDS due to a 7q21.13-q21.3 microdeletion complicated by early-onset multiple cerebral cavernous malformations (CCMs). The patient presented with myoclonus and dystonia at two and eight years of age, respectively. In addition to MDS, the patient developed growth hormone (GH) deficiency and mild intellectual disability. Magnetic resonance imaging of the brain showed multiple CCMs. Array-based comparative genomic hybridization revealed 7q21.13-21.3 microdeletion. The deletion size was 4.11 Mb, which included SCGE and KRIT1. After the introduction of zonisamide, both myoclonus and dystonia showed improvement, and GH therapy led to an increase in patient height. In cases of MDS, multiple early-onset CCMs and GH deficiency may occur; moreover, careful follow-up management may be necessary., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Matsubara et al.)
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- 2024
- Full Text
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15. Novel KRIT1/CCM1 mutation in a patient with retinal cavernous hemangioma and cerebral cavernous malformation
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Reddy, Shantan, Gorin, Michael B., McCannel, Tara A., Tsui, Irena, and Straatsma, Bradley R.
- Subjects
Medicine & Public Health ,Ophthalmology ,Cerebral cavernous malformation ,KRIT1 ,Mutation ,Retinal cavernous hemangioma - Abstract
Retinal cavernous hemangiomas are rare vascular anomalies, and can be associated with cerebral cavernous malformations (CCM). Distinct mutations have been reported in patients who have both CCMs and retinal cavernous hemangiomas.Fluorescein angiography, spectral domain optical coherence tomography, and genetic testing were performed on a patient with a retinal cavernous hemangioma and a CCM.Our patient was heterozygous in the KRIT1/CCM1 gene for a frameshift mutation, c.1088delC. This would be predicted to result in premature protein termination.We have identified a novel mutation in the KRIT1/CCM1 gene in a patient with both CCM and retinal cavernous hemangioma. We hypothesize that the occurrence of retinal cavernous hemangiomas and CCMs is underlaid by a common mechanism present in the KRIT1/CCM1 gene.
- Published
- 2010
16. Glucose-sensing microRNA-21 disrupts ROS homeostasis and impairs antioxidant responses in cellular glucose variability
- Author
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Lucia La Sala, Simona Mrakic-Sposta, Stefano Micheloni, Francesco Prattichizzo, and Antonio Ceriello
- Subjects
miR-21 ,ROS homeostasis ,KRIT1 ,SOD2 ,Superoxide anion ,Mitochondrial dysfunction ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Antioxidant enzymes play a fundamental role in counteracting oxidative stress induced by high glucose. Although mitochondrial superoxide dismutase (SOD2) is the principal defence against the toxicity of superoxide anions, the mechanism of its inactivation in diabetic subjects is still poorly understood. Recently, microRNA-21 has been associated with diabetes, although its function remains unclear. We sought to explore the mechanism underlying defective SOD2 antioxidant response in HUVECs during exposures to constant high glucose and oscillating glucose (as glucose variability model, GV) and the role of miR-21 in increasing the susceptibility to oxidative stress by disrupting reactive oxygen species (ROS) homeostasis. Methods HUVECs exposed for 1 week to constant high glucose and GV were subjected to quantitative electron paramagnetic resonance for ROS measurements. Superoxide anions, SOD2 protein levels and mitochondrial membrane potential (ΔΨm) were also evaluated. Endogenous miR-21 and its putative ROS-homeostatic target genes (KRIT1, FoxO1, NFE2L2 and SOD2) were tested using mimic-miR-21 and quantified by qPCR. Luciferase assays were performed to test miR-21/3′-UTR-SOD2 binding. Results We observed upregulation of microRNA-21, overproduction of superoxide anions and total ROS generation, depolarisation of the mitochondrial membrane potential (ΔΨm) and defective SOD2 antioxidant response in HUVECs subjected to constant high glucose and GV exposures. We also found that exogenous mimic-microRNA-21 targeted putative microRNA-21 ROS-homeostatic target genes, e.g., KRIT1, NRF2 and SOD2, which were significantly downregulated. All these effects were reverted by a microRNA-21 inhibitor, which improved SOD2 and KRIT1 expression, reduced the levels of ROS production and ameliorated ΔΨm. Conclusions Our data demonstrate the association of microRNA-21 with oscillating and high glucose and early mitochondrial dysfunction. We found that microRNA-21 may promote the suppression of homeostatic signalling that normally limits ROS damage. These data provide novel clues about the inhibition of microRNA-21 as a new therapeutic approach to protect against cellular oxidative injury in glucose variability and diabetes.
- Published
- 2018
- Full Text
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17. Familial Cerebral Cavernous Malformation Syndrome with Concomitant Fourth Ventricular Ependymoma: True Association or Mere Coincidence?
- Author
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Algattas, Hanna, Abou-Al-Shaar, Hussam, Mendelson, Michael, Arnold, Georgianne L., Felker, James, Meade, Julia, and Greene, Stephanie
- Subjects
- *
EPENDYMOMA , *HUMAN abnormalities , *PATHOLOGY , *COINCIDENCE , *ARNOLD-Chiari deformity , *THYROID cancer , *THYROTROPIN - Abstract
Familial cerebral cavernous malformation syndromes are most commonly caused by mutations in one of three genes. The overlap of these genetic malformations with other acquired neoplastic lesions and congenital malformations is still under investigation. To the best of our knowledge, the concurrent occurrence of familial cavernous malformations and ependymoma has not been previously reported in the literature. Herein, we describe a patient with familial cerebral cavernous malformation syndrome and posterior fossa ependymoma. A 17-year-old asymptomatic male was referred to our outpatient neurosurgery clinic after genetic testing identified a familial KRIT1 (CCM1) mutation. The patient's sister had presented with a seizure disorder previously; multiple cavernous malformations were discovered, and a symptomatic large cavernous malformation required a craniotomy for resection. Two years later, she was diagnosed with follicular thyroid cancer due to HRAS (c.182A>G) mutation. The patient and his sister were found to have a novel germline KRIT1 disease-causing variant (c.1739deletion, p.ASN580Ilefs*2) and a variant of uncertain significance, potentially pathogenic (c.1988 A>G, p.Asn663Ser) in cis in CCM1 (KRIT1), of paternal inheritance. Due to the presence of genetic abnormalities, the patient underwent screening imaging of his neuraxis. Multiple cavernous malformations were identified, as was an incidental fourth ventricular mass. Resection of the fourth ventricular lesion was performed, and histopathological examination was consistent with ependymoma. We report a unique case of posterior fossa ependymoma in an individual with a familial cerebral cavernous malformation syndrome and a novel genetic abnormality in KRIT1. The association of these two findings may be valuable in determining a potential genetic association between the two pathologies and elucidating the pathogenesis of both cavernous malformations and ependymomas. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
18. Molecular diagnostic workflow, clinical interpretation of sequence variants, and data repository procedures in 140 individuals with familial cerebral cavernous malformations.
- Author
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Fusco, Carmela, Copetti, Massimiliano, Mazza, Tommaso, Amoruso, Luigi, Mastoianno, Sandra, Nardella, Grazia, Guarnieri, Vito, Micale, Lucia, D'Agruma, Leonardo, and Castori, Marco
- Abstract
Familial cerebral cavernous malformation (FCCM) is an autosomal dominant vascular disorder caused by heterozygous deleterious variants in KRIT1, CCM2 or PDCD10. In a previous study, we presented the clinical and molecular findings in 140 FCCM individuals. In the present work, we report supporting information on (a) applied diagnostic workflow; (b) clinical significance of molecular findings according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology recommendations; (c) standardization of molecular and clinical data according to the Human Phenotype Ontology; (d) preliminary genotype‐phenotype correlations on a subgroup of patients by considering sex, age at diagnosis, neurological symptoms, and number and anatomical site(s) of vascular anomalies; (e) datasets submitted to the Leiden Open Variation Database. An overview of the changes of our diagnostic approach before and after the transition to next‐generation sequencing is also reported. This work presents the full procedure that we apply for molecular testing, data interpretation and storing in public databases in FCCM. Data Repository Information: LOVD ID number: 02515 https://databases.lovd.nl/shared/individuals/00165057 https://databases.lovd.nl/shared/individuals/00165058 https://databases.lovd.nl/shared/individuals/00165059 https://databases.lovd.nl/shared/individuals/00165061 https://databases.lovd.nl/shared/individuals/00165062 https://databases.lovd.nl/shared/individuals/00165063 https://databases.lovd.nl/shared/individuals/00165064 https://databases.lovd.nl/shared/individuals/00165065 https://databases.lovd.nl/shared/individuals/00165066 https://databases.lovd.nl/shared/individuals/00165067 https://databases.lovd.nl/shared/individuals/00165068 https://databases.lovd.nl/shared/individuals/00165069 https://databases.lovd.nl/shared/individuals/00165070 https://databases.lovd.nl/shared/individuals/00165071 https://databases.lovd.nl/shared/individuals/00165072 https://databases.lovd.nl/shared/individuals/00165073 https://databases.lovd.nl/shared/individuals/00165074 https://databases.lovd.nl/shared/individuals/00165075 https://databases.lovd.nl/shared/individuals/00165076 https://databases.lovd.nl/shared/individuals/00165077 https://databases.lovd.nl/shared/individuals/00165080 https://databases.lovd.nl/shared/individuals/00165083 https://databases.lovd.nl/shared/individuals/00165082 https://databases.lovd.nl/shared/individuals/00165700 https://databases.lovd.nl/shared/individuals/00165085 https://databases.lovd.nl/shared/individuals/00165081 https://databases.lovd.nl/shared/individuals/00165079 https://databases.lovd.nl/shared/individuals/00165043 https://databases.lovd.nl/shared/individuals/00165078 [ABSTRACT FROM AUTHOR]
- Published
- 2019
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19. MicroRNA-1185 Induces Endothelial Cell Apoptosis by Targeting UVRAG and KRIT1
- Author
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Haoyuan Deng, Xia Chu, Zhenfeng Song, Xinrui Deng, Huan Xu, Yaxin Ye, Songtao Li, Qiao Zhang, Changhao Sun, and Ying Li
- Subjects
MiR-1185 ,Apoptosis ,UVRAG ,KRIT1 ,Endothelium ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: Atherosclerosis is a multifactorial chronic disease and is the main cause of death and impairment in the world. Endothelial injury and apoptosis play a crucial role in the onset and development of atherosclerosis. MicroRNAs (miRNAs) have been proven to be involved in the pathogenesis of atherosclerosis. However, studies of the functional role of apoptosis-related miRNAs in the endothelium during atherogenesis are limited. Methods: Cell injury and apoptosis were measured in five types of cells transfected with miR-1185 or co-transfected with miR-1185 and its inhibitor. Bioinformatics analysis and a luciferase reporter assay were used to confirm the targets of miR-1185. The effects of the targets of miR-1185 on endothelial apoptosis were determined using small-interfering RNA. Results: In this study, we first report that miR-1185 significantly promoted apoptosis in endothelial cells but not in vascular smooth muscle cells and macrophages. A mechanistic analysis showed that ultraviolet irradiation resistance-associated gene (UVRAG) and krev1 interaction trapped gene 1 (KRIT1), targets of miR-1185, mediated miR-1185-induced endothelial cell apoptosis. Conclusion: The results revealed the impact of miR-1185 on endothelial apoptosis, suggesting that miR-1185 may be a potential target for the prevention and treatment of atherosclerosis.
- Published
- 2017
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20. Molecular Genetic Features of Cerebral Cavernous Malformations (CCM) Patients: An Overall View from Genes to Endothelial Cells
- Author
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Giulia Riolo, Claudia Ricci, and Stefania Battistini
- Subjects
cerebral cavernous malformation ,CCM ,KRIT1 ,CCM2 ,PDCD10 ,protein structure ,Cytology ,QH573-671 - Abstract
Cerebral cavernous malformations (CCMs) are vascular lesions that affect predominantly microvasculature in the brain and spinal cord. CCM can occur either in sporadic or familial form, characterized by autosomal dominant inheritance and development of multiple lesions throughout the patient’s life. Three genes associated with CCM are known: CCM1/KRIT1 (krev interaction trapped 1), CCM2/MGC4607 (encoding a protein named malcavernin), and CCM3/PDCD10 (programmed cell death 10). All the mutations identified in these genes cause a loss of function and compromise the protein functions needed for maintaining the vascular barrier integrity. Loss of function of CCM proteins causes molecular disorganization and dysfunction of endothelial adherens junctions. In this review, we provide an overall vision of the CCM pathology, starting with the genetic bases of the disease, describing the role of the proteins, until we reach the cellular level. Thus, we summarize the genetics of CCM, providing a description of CCM genes and mutation features, provided an updated knowledge of the CCM protein structure and function, and discuss the molecular mechanisms through which CCM proteins may act within endothelial cells, particularly in endothelial barrier maintenance/regulation and in cellular signaling.
- Published
- 2021
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21. A single‐center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion.
- Author
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Nardella, Grazia, Visci, Grazia, Guarnieri, Vito, Castellana, Stefano, Biagini, Tommaso, Bisceglia, Luigi, Palumbo, Orazio, Trivisano, Marina, Vaira, Carmela, Scerrati, Massimo, Debrasi, Davide, D'Angelo, Vincenzo, Carella, Massimo, Merla, Giuseppe, Mazza, Tommaso, Castori, Marco, D'Agruma, Leonardo, and Fusco, Carmela
- Abstract
Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single‐center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4–10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM. Cerebral cavernous malformation is a capillary malformation with three genes associated KRIT1, CCM2 and PDCD10. From a pool of 317 CCM index patients we found germline variants in either of the three genes. Effects of the 3 novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4–10, on patient's fibroblasts, which showed reduction of interactions between CCM proteins and impaired autophagy process. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for CCM management. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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22. Cerebral Cavernous Malformation: A Portuguese Family with a Novel CCM1 Mutation
- Author
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João Pedro Marto, Inês Gil, Sofia Calado, and Miguel Viana-Baptista
- Subjects
CCM1 mutation ,KRIT1 ,Cerebral cavernous malformation ,Cavernoma ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Introduction: Cerebral cavernous malformation (CCM) is a vascular disorder characterized by the presence of central nervous system cavernomas. In familial forms, mutations in three genes (CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10) were identified. We describe a Portuguese family harboring a novel CCM1 mutation. Case Presentation: The proband is a woman who at the age of 55 years started to have complex partial seizures and episodic headache. Although nothing was found during her neurological examination, brain MRI showed bilateral, supra- and infratentorial cavernomas. She had a sister who, at the age 61 years, suffered a tonic-clonic seizure. Neurological examination was normal and imaging investigation demonstrated a right frontal intracerebral hemorrhage and multiple cavernomas. In the following years, she suffered several complex partial seizures and had a new intracerebral hemorrhage located in the right temporal lobe. Genetic analysis was performed and a novel nucleotide substitution, i.e. c.1927C>T (p.Gln643*) within the exon 17 of the CCM1 gene, was detected in both sisters. The substitution encodes a stop codon, with a consequent truncated KRIT1 protein, therefore supporting its pathogenic role. Further affected family members were detected, suggesting an autosomal dominant pattern of inheritance. Conclusion: We report a Portuguese family with a novel CCM1 (KRIT1) mutation – c.1927C>T (p.Gln643*). A better knowledge of the phenotype-genotype correlation is needed to improve the management of CCM patients.
- Published
- 2016
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23. Response to: Concern regarding classification of c.703G>A/p.Gly235Arg as a novel missense variant in KRIT1 gene.
- Author
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Fusco, Carmela, Micale, Lucia, and Castori, Marco
- Published
- 2020
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24. Corrigendum: Cerebral Cavernous Malformations: Review of the Genetic and Protein–Protein Interactions Resulting in Disease Pathogenesis
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Jacob F. Baranoski, M. Yashar S. Kalani, Colin J. Przybylowski, and Joseph M. Zabramski
- Subjects
cavernous malformation ,CCM ,CCM1 ,CCM2 ,CCM3 ,KRIT1 ,Surgery ,RD1-811 - Published
- 2017
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25. Cerebral cavernous malformations: Review of the genetic and protein-protein interactions resulting in disease pathogenesis
- Author
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Jacob F. Baranoski, M. Yashar S. Kalani, and Joseph M. Zabramski
- Subjects
gene ,molecular genetics ,CCM ,Krit1 ,CCM1 ,CCM2 ,Surgery ,RD1-811 - Abstract
Mutations in the genes KRIT1, CCM2, and PDCD10 are known to result in the formation of cerebral cavernous malformations (CCMs). CCMs are intracranial lesions comprised of aberrantly enlarged cavernous endothelial channels that can result in cerebral hemorrhage, seizures, and neurologic deficits. Although these genes have been known to be associated with CCMs since the 1990s, numerous discoveries have been made that better elucidate how they and their subsequent protein products are involved in CCM pathogenesis. Since our last review of the molecular genetics of CCM pathogenesis in 2012, breakthroughs include a more thorough understanding of the protein structures of the gene products, involvement with integrin proteins and MEKK3 signaling pathways, the importance of CCM2-PDCD10 interactions, and others. In this review, we highlight the advances that further our understanding of the gene to protein to disease relationships of CCMs.
- Published
- 2016
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26. KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction
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Francesco Vieceli Dalla Sega, Raffaella Mastrocola, Giorgio Aquila, Francesca Fortini, Claudia Fornelli, Alessia Zotta, Alessia S. Cento, Andrea Perrelli, Enrica Boda, Antonio Pannuti, Saverio Marchi, Paolo Pinton, Roberto Ferrari, Paola Rizzo, and Saverio Francesco Retta
- Subjects
cerebral cavernous malformation (ccm) ,krit1 ,endothelial dysfunction (ed) ,notch signaling ,notch1 ,oxidative stress ,ros ,atherosclerosis ,vcam-1 ,icam-1 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Loss-of-function mutations of the gene encoding Krev interaction trapped protein 1 (KRIT1) are associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries and affecting 0.5% of the human population. However, growing evidence demonstrates that KRIT1 is implicated in the modulation of major redox-sensitive signaling pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, suggesting that its loss-of-function mutations may have pathological effects not limited to CCM disease. The aim of this study was to address whether KRIT1 loss-of-function predisposes to the development of pathological conditions associated with enhanced endothelial cell susceptibility to oxidative stress and inflammation, such as arterial endothelial dysfunction (ED) and atherosclerosis. Silencing of KRIT1 in human aortic endothelial cells (HAECs), coronary artery endothelial cells (HCAECs), and umbilical vein endothelial cells (HUVECs) resulted in increased expression of endothelial proinflammatory adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and in enhanced susceptibility to tumor necrosis factor alpha (TNF-α)-induced apoptosis. These effects were associated with a downregulation of Notch1 activation that could be rescued by antioxidant treatment, suggesting that they are consequent to altered intracellular redox homeostasis induced by KRIT1 loss-of-function. Furthermore, analysis of the aorta of heterozygous KRIT1+/− mice fed a high-fructose diet to induce systemic oxidative stress and inflammation demonstrated a 1.6-fold increased expression of VCAM-1 and an approximately 2-fold enhanced fat accumulation (7.5% vs 3.6%) in atherosclerosis-prone regions, including the aortic arch and aortic root, as compared to corresponding wild-type littermates. In conclusion, we found that KRIT1 deficiency promotes ED, suggesting that, besides CCM, KRIT1 may be implicated in genetic susceptibility to the development of atherosclerotic lesions.
- Published
- 2019
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27. KRIT1 Loss-Of-Function Associated with Cerebral Cavernous Malformation Disease Leads to Enhanced S-Glutathionylation of Distinct Structural and Regulatory Proteins
- Author
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Laura Cianfruglia, Andrea Perrelli, Claudia Fornelli, Alessandro Magini, Stefania Gorbi, Anna Maria Salzano, Cinzia Antognelli, Francesca Retta, Valerio Benedetti, Paola Cassoni, Carla Emiliani, Giovanni Principato, Andrea Scaloni, Tatiana Armeni, and Saverio Francesco Retta
- Subjects
cerebral cavernous malformations ,KRIT1 ,oxidative stress ,altered redox homeostasis and signaling ,oxidative post-translational modifications ,protein S-glutathionylation ,redox proteomics ,mass spectrometry ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Loss-of-function mutations in the KRIT1 gene are associated with the pathogenesis of cerebral cavernous malformations (CCMs), a major cerebrovascular disease still awaiting therapies. Accumulating evidence demonstrates that KRIT1 plays an important role in major redox-sensitive mechanisms, including transcriptional pathways and autophagy, which play major roles in cellular homeostasis and defense against oxidative stress, raising the possibility that KRIT1 loss has pleiotropic effects on multiple redox-sensitive systems. Using previously established cellular models, we found that KRIT1 loss-of-function affects the glutathione (GSH) redox system, causing a significant decrease in total GSH levels and increase in oxidized glutathione disulfide (GSSG), with a consequent deficit in the GSH/GSSG redox ratio and GSH-mediated antioxidant capacity. Redox proteomic analyses showed that these effects are associated with increased S-glutathionylation of distinct proteins involved in adaptive responses to oxidative stress, including redox-sensitive chaperonins, metabolic enzymes, and cytoskeletal proteins, suggesting a novel molecular signature of KRIT1 loss-of-function. Besides providing further insights into the emerging pleiotropic functions of KRIT1, these findings point definitively to KRIT1 as a major player in redox biology, shedding new light on the mechanistic relationship between KRIT1 loss-of-function and enhanced cell sensitivity to oxidative stress, which may eventually lead to cellular dysfunctions and CCM disease pathogenesis.
- Published
- 2019
- Full Text
- View/download PDF
28. Case Report: A novel heterozygous nonsense mutation in KRIT1 cause hereditary cerebral cavernous malformation.
- Author
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Liu Z, Guo K, Hu X, and Zhang X
- Abstract
Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system and mainly characterized by enlarged capillary cavities without intervening brain parenchyma. Genetic studies have identified three disease-causing genes ( CCM1/KRIT1 , CCM2/MGC4607 and CCM3/PDCD10 ) responsible for CCM. Here, we characterized a four-generation family diagnosed with CCM and identified a novel heterozygous mutation c.1159C>T, p.Q387X in KRIT1 gene by whole exome sequencing and Sanger sequencing. The Q387X mutation resulted in premature termination of KRIT1 protein, which was predicted to be deleterious by the ACMG/AMP 2015 guideline. Our results provide novel genetic evidence support that KRIT1 mutations cause CCM, and are helpful to the treatment and genetic diagnosis of CCM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Guo, Hu and Zhang.)
- Published
- 2023
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29. Cerebral Cavernous Malformation: A Portuguese Family with a Novel CCM1 Mutation.
- Author
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Marto, João Pedro, Gil, Inês, Calado, Sofia, and Viana-Baptista, Miguel
- Subjects
- *
GENETIC mutation , *NEUROLOGICAL disorders , *MAGNETIC resonance imaging of the brain , *VASCULAR diseases , *PHENOTYPES - Abstract
Introduction: Cerebral cavernous malformation (CCM) is a vascular disorder characterized by the presence of central nervous system cavernomas. In familial forms, mutations in three genes (CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10) were identified. We describe a Portuguese family harboring a novel CCM1 mutation. Case Presentation: The proband is a woman who at the age of 55 years started to have complex partial seizures and episodic headache. Although nothing was found during her neurological examination, brain MRI showed bilateral, supra- and infratentorial cavernomas. She had a sister who, at the age 61 years, suffered a tonic-clonic seizure. Neurological examination was normal and imaging investigation demonstrated a right frontal intracerebral hemorrhage and multiple cavernomas. In the following years, she suffered several complex partial seizures and had a new intracerebral hemorrhage located in the right temporal lobe. Genetic analysis was performed and a novel nucleotide substitution, i.e. c.1927C>T (p.Gln643*) within the exon 17 of the CCM1 gene, was detected in both sisters. The substitution encodes a stop codon, with a consequent truncated KRIT1 protein, therefore supporting its pathogenic role. Further affected family members were detected, suggesting an autosomal dominant pattern of inheritance. Conclusion: We report a Portuguese family with a novel CCM1 (KRIT1) mutation - c.1927C>T (p.Gln643*). A better knowledge of the phenotype-genotype correlation is needed to improve the management of CCM patients. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
30. Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans.
- Author
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Yuehua Wei and Kenyon, Cynthia
- Subjects
- *
HORMESIS , *CAENORHABDITIS elegans , *REACTIVE oxygen species , *HYDROGEN sulfide , *GERM cells - Abstract
In Caenorhabditis elegans, removing germ cells slows aging and extends life. Here we show that transcription factors that extend life and confer protection to age-related protein-aggregation toxicity are activated early in adulthood in response to a burst of reactive oxygen species (ROS) and a shift in sulfur metabolism. Germline loss triggers H2S production, mitochondrial biogenesis, and a dynamic pattern of ROS in specific somatic tissues. A cytoskeletal protein, KRI-1, plays a key role in the generation of H2S and ROS. These kri-1-dependent redox species, in turn, promote life extension by activating SKN-1/Nrf2 and the mitochondrial unfolded-protein response, respectively. Both H2S and, remarkably, kri-1-dependent ROS are required for the life extension produced by low levels of the superoxide- generator paraquat and by a mutation that inhibits respiration. Together our findings link reproductive signaling tomitochondria and define an inducible, kri-1-dependent redox-signaling module that can be invoked in different contexts to extend life and counteract proteotoxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
31. Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6.
- Author
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Meliton, Angelo, Fanyong Meng, Yufeng Tian, Shah, Alok A., Birukova, Anna A., and Birukov, Konstantin G.
- Published
- 2015
- Full Text
- View/download PDF
32. Inhibition of the HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells.
- Author
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Lopez-Ramirez, Miguel Alejandro, Lopez-Ramirez, Miguel Alejandro, McCurdy, Sara, Li, Wenqing, Haynes, Mark K, Hale, Preston, Francisco, Karol, Oukoloff, Killian, Bautista, Matthew, Choi, Chelsea HJ, Sun, Hao, Gongol, Brendan, Shyy, John Y, Ballatore, Carlo, Sklar, Larry A, Gingras, Alexandre R, Lopez-Ramirez, Miguel Alejandro, Lopez-Ramirez, Miguel Alejandro, McCurdy, Sara, Li, Wenqing, Haynes, Mark K, Hale, Preston, Francisco, Karol, Oukoloff, Killian, Bautista, Matthew, Choi, Chelsea HJ, Sun, Hao, Gongol, Brendan, Shyy, John Y, Ballatore, Carlo, Sklar, Larry A, and Gingras, Alexandre R
- Abstract
The transmembrane protein heart of glass1 (HEG1) directly binds to and recruits Krev interaction trapped protein 1 (KRIT1) to endothelial junctions to form the HEG1-KRIT1 protein complex that establishes and maintains junctional integrity. Genetic inactivation or knockdown of endothelial HEG1 or KRIT1 leads to the upregulation of transcription factors Krüppel-like factors 4 and 2 (KLF4 and KLF2), which are implicated in endothelial vascular homeostasis; however, the effect of acute inhibition of the HEG1-KRIT1 interaction remains incompletely understood. Here, we report a high-throughput screening assay and molecular design of a small-molecule HEG1-KRIT1 inhibitor to uncover acute changes in signaling pathways downstream of the HEG1-KRIT1 protein complex disruption. The small-molecule HEG1-KRIT1 inhibitor 2 (HKi2) was demonstrated to be a bona fide inhibitor of the interaction between HEG1 and KRIT1 proteins, by competing orthosterically with HEG1 through covalent reversible interactions with the FERM (4.1, ezrin, radixin, and moesin) domain of KRIT1. The crystal structure of HKi2 bound to KRIT1 FERM revealed that it occupies the same binding pocket on KRIT1 as the HEG1 cytoplasmic tail. In human endothelial cells (ECs), acute inhibition of the HEG1-KRIT1 interaction by HKi2 increased KLF4 and KLF2 mRNA and protein levels, whereas a structurally similar inactive compound failed to do so. In zebrafish, HKi2 induced expression of klf2a in arterial and venous endothelium. Furthermore, genome-wide RNA transcriptome analysis of HKi2-treated ECs under static conditions revealed that, in addition to elevating KLF4 and KLF2 expression, inhibition of the HEG1-KRIT1 interaction mimics many of the transcriptional effects of laminar blood flow. Furthermore, HKi2-treated ECs also triggered Akt signaling in a phosphoinositide 3-kinase (PI3K)-dependent manner, as blocking PI3K activity blunted the Akt phosphorylation induced by HKi2. Finally, using an in vitro colocalization assay
- Published
- 2021
33. Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants
- Author
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Marco Castori, Marilena Carmela Di Giacomo, Leonardo D'Agruma, Grazia Nardella, Antonio Petracca, Carmela Fusco, Stefano Gambardella, Stefania Zampatti, Nicola Paciello, Silvia Lanfranconi, Lucia Micale, and Dario Ronchi
- Subjects
0301 basic medicine ,Hemangioma, Cavernous, Central Nervous System ,Vascular homeostasis ,KRIT1 ,In silico ,PDCD10 ,RNA Splicing ,Central nervous system ,Complex formation ,030105 genetics & heredity ,Biology ,Frameshift mutation ,cerebral cavernous malformations ,03 medical and health sciences ,splicing ,Proto-Oncogene Proteins ,Genetics ,medicine ,Humans ,mRNA analysis ,RNA, Messenger ,KRIT1 Protein ,Genetics (clinical) ,Messenger RNA ,Vascular malformation ,Membrane Proteins ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,RNA splicing ,Mutation ,Apoptosis Regulatory Proteins - Abstract
Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system which may occur sporadically or segregate within families due to heterozygous variants in KRIT1/CCM1, MGC4607/CCM2 or PDCD10/CCM3. Intronic variants are not uncommon in familial CCM, but their clinical interpretation is often hampered by insufficient data supporting in silico predictions. Here, the mRNA analysis for two intronic unpublished variants (KRIT1 c.1147-7 T > G and PDCD10 c.395 + 2 T > G) and three previously published variants in KRIT1 but without data supporting their effects was carried out. This study demonstrated that all variants can induce a frameshift with the lack of residues located in the C-terminal regions and involved in protein-protein complex formation, which is essential for vascular homeostasis. These results support the introduction of mRNA analysis in the diagnostic pathway of familial CCM and expand the knowledge of abnormal splicing patterning in this disorder.
- Published
- 2021
34. Proteomic analysis reveals KRIT1 as a modulator for the antioxidant effects of valproic acid in human bone-marrow mesenchymal stromal cells.
- Author
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Jung, Kyoung Hwa, Han, Dal Mu Ri, Jeong, Sin-Gu, Choi, Mi Ran, Chai, Young Gyu, and Cho, Goang-Won
- Subjects
- *
MESENCHYMAL stem cells , *OXIDATIVE stress , *VALPROIC acid , *RAP1 proteins , *HOMEOSTASIS , *MATRIX-assisted laser desorption-ionization , *TIME-of-flight mass spectrometry , *FORKHEAD transcription factors , *PHYSIOLOGY , *PREVENTION - Abstract
Valproic acid (VPA) protects human bone marrow-mesenchymal stromal cells (hBM-MSCs) against oxidative stress and improves their migratory ability through increasing the secretion of trophic factors. This suggests that VPA may be an excellent candidate for improving stem cell function. However, the molecular mechanisms of VPA in BM-MSCs are not known. In this study, we used a proteomic approach to investigate VPA-associated targets under oxidative stress conditions. Krev/Rap1 interaction Trapped-1 (KRIT1), a modulator for the homeostasis of intracellular reactive oxygen species (ROS), was identified as a target protein by two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) analyses. The up-regulation of KRIT1 and its target proteins (SOD2 and FoxO1) with VPA treatment of hBM-MSCs was revealed by qPCR and immunoblot analysis. Damage from oxidative stress was reduced in VPA-pretreated BM-MSCs, which was also confirmed by qPCR and immunoblot analysis. In addition, increased in intracellular ROS by H2O2were also reduced by VPA pretreatment in BM-MSCs. This suggests that VPA reduces intracellular ROS level by the modulation of KRIT1 and its correlated proteins, FoxO1, SOD2, and cyclin D1. Thus, this study is the first to provide evidence that VPA modulates KRIT1 and intracellular ROS in BM-MSCs. [ABSTRACT FROM PUBLISHER]
- Published
- 2015
- Full Text
- View/download PDF
35. Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations.
- Author
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Riant, F., Odent, S., Cecillon, M., Pasquier, L., de Baracé, C., Carney, M.P., and Tournier‐Lasserve, E.
- Subjects
- *
HUMAN abnormalities , *MEDICAL screening , *NUCLEOTIDE sequencing , *GENETIC code , *TISSUE wounds - Abstract
Loss-of-function mutations in CCM1/ KRIT1, CCM2/ MGC4607 and CCM3/ PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations ( CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments ( QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
36. Protein kinase C alpha regulates the nucleocytoplasmic shuttling of KRIT1
- Author
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Andrea Scaloni, Elisa De Luca, Harsha Swamy, Anna Lisa Furfaro, Andrea Perrelli, Anna Maria Salzano, Angela Glading, Mariapaola Nitti, Mario Passalacqua, and Saverio Francesco Retta
- Subjects
Scaffold protein ,CCM1/KRIT1 ,Cerebral Cavernous Malformation (CCM) ,Nucleocytoplasmic shuttling ,PKC signaling ,PKCα ,PKCδ ,Phorbol esters ,Phosphoproteomics ,Redox signaling ,Protein Kinase C-alpha ,KRIT1 ,Regulator ,Active Transport, Cell Nucleus ,PKC alpha ,Biology ,PKC delta ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Gene silencing ,Humans ,Phosphorylation ,Protein kinase A ,KRIT1 Protein ,Protein kinase C ,Cerebral cavernous malformation ,HeLa Cells ,Tetradecanoylphorbol Acetate ,030304 developmental biology ,Cell Nucleus ,0303 health sciences ,Cell Biology ,Active Transport ,Cell biology ,Cytoplasm ,030217 neurology & neurosurgery ,Research Article - Abstract
KRIT1 is a scaffolding protein that regulates multiple molecular mechanisms, including cell–cell and cell–matrix adhesion, and redox homeostasis and signaling. However, rather little is known about how KRIT1 is itself regulated. KRIT1 is found in both the cytoplasm and the nucleus, yet the upstream signaling proteins and mechanisms that regulate KRIT1 nucleocytoplasmic shuttling are not well understood. Here, we identify a key role for protein kinase C (PKC) in this process. In particular, we found that PKC activation promotes the redox-dependent cytoplasmic localization of KRIT1, whereas inhibition of PKC or treatment with the antioxidant N-acetylcysteine leads to KRIT1 nuclear accumulation. Moreover, we demonstrated that the N-terminal region of KRIT1 is crucial for the ability of PKC to regulate KRIT1 nucleocytoplasmic shuttling, and may be a target for PKC-dependent regulatory phosphorylation events. Finally, we found that silencing of PKCα, but not PKCδ, inhibits phorbol 12-myristate 13-acetate (PMA)-induced cytoplasmic enrichment of KRIT1, suggesting a major role for PKCα in regulating KRIT1 nucleocytoplasmic shuttling. Overall, our findings identify PKCα as a novel regulator of KRIT1 subcellular compartmentalization, thus shedding new light on the physiopathological functions of this protein., Summary: A novel role for PKC signaling in triggering Ser/Thr phosphorylation and regulating nucleocytoplasmic shuttling of KRIT1, a major protein with pleiotropic functions associated with human diseases.
- Published
- 2021
37. Molecular genetic analysis of cerebral cavernous malformations: an update
- Author
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Giulia Riolo, Stefania Battistini, and Claudia Ricci
- Subjects
De novo mutation ,KRIT1 ,Phenotype-genotype correlation ,Genetic counseling ,Penetrance ,Biology ,Bioinformatics ,Cerebral cavernous malformations ,Molecular analysis ,PDCD10 gene variants ,CCM2 ,Screening methods - Published
- 2021
38. Non-autonomous effects of CCM genes loss
- Author
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Lorenza Trabalzini and Federica Finetti
- Subjects
Genetics ,Cerebrovascular disease, cerebral cavernous malformation, KRIT1, CCM1, CCM2, CCM3, endothelial cells, mosaicism ,mosaicism ,KRIT1 ,cerebral cavernous malformation ,Biology ,Cerebrovascular disease ,CCM1 ,Gene ,CCM3 ,endothelial cells ,CCM2 - Published
- 2021
39. Molecular genetic features of cerebral cavernous malformations (CCM) patients: An overall view from genes to endothelial cells
- Author
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Claudia Ricci, Stefania Battistini, and Giulia Riolo
- Subjects
Programmed cell death 10 ,Cell signaling ,KRIT1 ,Endothelial cells ,PDCD10 ,Disease ,Review ,medicine.disease_cause ,Adherens junction ,Protein structure ,Proto-Oncogene Proteins ,medicine ,Humans ,Genetic Predisposition to Disease ,lcsh:QH301-705.5 ,Gene ,KRIT1 Protein ,Loss function ,CCM2 ,CCM ,Central Nervous System Vascular Malformations ,Mutation ,Cerebral cavernous malformation ,biology ,Microvessel lesions ,Brain ,Membrane Proteins ,General Medicine ,Signaling complex ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Endothelial Cells ,Phenotype ,Signal Transduction ,Cell biology ,lcsh:Biology (General) ,biology.gene - Abstract
Cerebral cavernous malformations (CCMs) are vascular lesions that affect predominantly microvasculature in the brain and spinal cord. CCM can occur either in sporadic or familial form, characterized by autosomal dominant inheritance and development of multiple lesions throughout the patient’s life. Three genes associated with CCM are known: CCM1/KRIT1 (krev interaction trapped 1), CCM2/MGC4607 (encoding a protein named malcavernin), and CCM3/PDCD10 (programmed cell death 10). All the mutations identified in these genes cause a loss of function and compromise the protein functions needed for maintaining the vascular barrier integrity. Loss of function of CCM proteins causes molecular disorganization and dysfunction of endothelial adherens junctions. In this review, we provide an overall vision of the CCM pathology, starting with the genetic bases of the disease, describing the role of the proteins, until we reach the cellular level. Thus, we summarize the genetics of CCM, providing a description of CCM genes and mutation features, provided an updated knowledge of the CCM protein structure and function, and discuss the molecular mechanisms through which CCM proteins may act within endothelial cells, particularly in endothelial barrier maintenance/regulation and in cellular signaling.
- Published
- 2021
40. KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun.
- Author
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Goitre, Luca, De Luca, Elisa, Braggion, Stefano, Trapani, Eliana, Guglielmotto, Michela, Biasi, Fiorella, Forni, Marco, Moglia, Andrea, Trabalzini, Lorenza, and Retta, Saverio Francesco
- Subjects
- *
PROTEIN metabolism , *JUN oncogenes , *CARCINOGENESIS , *CEREBROVASCULAR disease , *ANIMAL models in research , *GENETIC regulation , *BRAIN abnormalities , *GENETICS - Abstract
Abstract: Loss-of-function mutations in the KRIT1 gene (CCM1) have been associated with the pathogenesis of cerebral cavernous malformations (CCM), a major cerebrovascular disease. However, KRIT1 functions and CCM pathogenetic mechanisms remain incompletely understood. Indeed, recent experiments in animal models have clearly demonstrated that the homozygous loss of KRIT1 is not sufficient to induce CCM lesions, suggesting that additional factors are necessary to cause CCM disease. Previously, we found that KRIT1 is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent ROS-induced cellular dysfunctions, including a reduced ability to maintain a quiescent state. Here, we show that KRIT1 loss of function leads to enhanced expression and phosphorylation of the redox-sensitive transcription factor c-Jun, as well as induction of its downstream target COX-2, in both cellular models and human CCM tissues. Furthermore, we demonstrate that c-Jun upregulation can be reversed by either KRIT1 re-expression or ROS scavenging, whereas KRIT1 overexpression prevents forced upregulation of c-Jun induced by oxidative stimuli. Taken together with the reported role of c-Jun in vascular dysfunctions triggered by oxidative stress, our findings shed new light on the molecular mechanisms underlying KRIT1 function and CCM pathogenesis. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
41. KRIT1 as a possible new player in melanoma aggressiveness
- Author
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Federica Finetti, Jasmine Ercoli, Lorenza Trabalzini, Giuseppe Valacchi, Giuseppe Belmonte, Clelia Miracco, and Brittany Woodby
- Subjects
0301 basic medicine ,Scaffold protein ,Adult ,Male ,Cell signaling ,Inflammation ,KRIT1 ,Melanoma ,N-cadherin ,Tumor suppressor ,β-catenin ,Biophysics ,Down-Regulation ,Biochemistry ,NO ,03 medical and health sciences ,Cell Movement ,Cell Line, Tumor ,Medicine ,Humans ,Molecular Biology ,KRIT1 Protein ,beta Catenin ,Aged ,Cell Proliferation ,Aged, 80 and over ,Cell Nucleus ,030102 biochemistry & molecular biology ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,030104 developmental biology ,Gene Knockdown Techniques ,Cutaneous melanoma ,Cancer research ,Melanocytes ,Female ,KRIT1, Melanoma, Tumor suppressor, N-cadherin, Inflammation, β-catenin ,Skin cancer ,medicine.symptom ,Signal transduction ,business - Abstract
Krev interaction trapped protein 1 (KRIT1) is a scaffold protein known to form functional complexes with distinct proteins, including Malcavernin, PDCD10, Rap1 and others. It appears involved in several cellular signaling pathways and exerts a protective role against inflammation and oxidative stress. KRIT1 has been studied as a regulator of endothelial cell functions and represents a determinant in the pathogenesis of Cerebral Cavernous Malformation (CCM), a cerebrovascular disease characterized by the formation of clusters of abnormally dilated and leaky blood capillaries, which predispose to seizures, neurological deficits and intracerebral hemorrhage. Although KRIT1 is ubiquitously expressed, few studies have described its involvement in pathologies other than CCM including cancer. Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic propensity. Despite the numerous efforts made to define the signaling pathways activated during melanoma progression, the molecular mechanisms at the basis of melanoma growth, phenotype plasticity and resistance to therapies are still under investigation.
- Published
- 2020
42. Production of KRIT1-knockout and KRIT1-knockin Mouse Embryonic Fibroblasts as Cellular Models of CCM Disease
- Author
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Saverio Francesco Retta, Alessia Zotta, Andrea Perrelli, Claudia Fornelli, and Luca Goitre
- Subjects
0301 basic medicine ,Heterozygous and homozygous KRIT1 knockout mice ,Cerebral cavernous malformation (CCM) ,KRIT1 ,Population ,Cellular homeostasis ,CCM genes ,Cellular and animal models of CCM disease ,Cerebrovascular diseases ,KRIT1 knockout mouse embryonic fibroblast (MEF) cells ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,medicine ,education ,Transcription factor ,education.field_of_study ,Autophagy ,Cerebrovascular disorder ,Actin cytoskeleton ,Embryonic stem cell ,Cell biology ,030104 developmental biology ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
The development of distinct cellular and animal models has allowed the identification and characterization of molecular mechanisms underlying the pathogenesis of cerebral cavernous malformation (CCM) disease. This is a major cerebrovascular disorder of proven genetic origin, affecting 0.5% of the population. Three disease genes have been identified: CCM1/KRIT1, CCM2, and CCM3. These genes encode for proteins implicated in the regulation of major cellular structures and mechanisms, such as cell-cell and cell-matrix adhesion, actin cytoskeleton dynamics, and endothelial-to-mesenchymal transition, suggesting that they may act as pleiotropic regulators of cellular homeostasis. Indeed, accumulated evidence in cellular and animal models demonstrates that emerged pleiotropic functions of CCM proteins are mainly due to their ability to modulate redox-sensitive pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, thus contributing to the preservation of cellular homeostasis and stress defenses. In particular, we demonstrated that KRIT1 loss-of-function affects master regulators of cellular redox homeostasis and responses to oxidative stress, including major redox-sensitive transcriptional factors and antioxidant proteins, and autophagy, suggesting that altered redox signaling and oxidative stress contribute to CCM pathogenesis, and opening novel preventive and therapeutic perspectives.In this chapter, we describe materials and methods for isolation of mouse embryonic fibroblast (MEF) cells from homozygous KRIT1-knockout mouse embryos, and their transduction with a lentiviral vector encoding KRIT1 to generate cellular models of CCM disease that contributed significantly to the identification of pathogenetic mechanisms.
- Published
- 2020
43. Identification of a c.601C>G mutation in the CCM1 gene in a kindred with multiple skin, spinal and cerebral cavernous malformations.
- Author
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Haghighi, Alireza, Fathi, Davood, Shahbazi, Majid, Motahari, Mohammad-Mahdy, and Friedman, Bethany
- Subjects
- *
GENETIC mutation , *DYSPLASIA , *BRAIN diseases , *CHROMOSOME duplication , *CENTRAL nervous system abnormalities , *SYMPTOMS - Abstract
Abstract: Cerebral cavernous malformations (CCM) are congenital vascular anomalies predominantly of the central nervous system but may include lesions in other tissues such as the retina, skin, and liver. These hamartomatous dysplasias, generally occurring sporadically, consist of dynamic clustered convoluted capillary cavities without intervening brain parenchyma that may lead to headaches, seizures, paresis, cerebral hemorrhages and focal neurological deficits. Familial forms of CCM, inherited in an autosomal dominant manner with incomplete penetrance and variable expression, are attributed to mutations in three genes, CCM1, CCM2 and CCM3. Here, we report a kindred of Persian descent exhibiting a range of clinical symptoms and features that include seizures, multiple lesions of the brain and spinal cord, and severe hyperkeratotic cutaneous capillary–venous malformations. Sanger DNA sequencing and deletion/duplication testing of the CCM1, CCM2, and CCM3 genes in the proband revealed a CCM1 c.601C>G mutation. Targeted mutation analysis in family members confirmed that this mutation segregated with the disease in the family. This family illustrates the phenotypic heterogeneity that has been observed in other reported CCM-pedigrees and highlights the importance of genetic testing for early diagnosis in familial CCM. To our knowledge, this is the first genetic investigation of CCM in the Persian population. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
44. Cerebral cavernous malformation: Clinical report of two families with variable phenotype associated with KRIT1 mutation.
- Author
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Balasubramanian, Meena, Jain, Vani, Glover, Rhona C., Robertson, Lisa K., and Mordekar, Santosh R.
- Abstract
Abstract: We report two families with a variable presentation in association with a KRIT1 mutation. The index patient in Family 1 was a 9-year old girl who presented with left hemi-dystonia and a cerebral cavernous malformation was identified in the right lentiform nucleus. The maternal grandmother presented with a spinal cavernoma, which was operated at 35-years of age. The mother presented with intractable temporal lobe epilepsy in childhood and underwent temporal lobe resection at 27-years of age. The second family has also presented variably with the youngest member of this family presenting with generalised tonic-clonic seizures at 18-months of age. We report both these families with variable presentation of an autosomal dominant condition and describe the phenotypic presentation in both these families in further detail and review the published literature on this condition. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
45. miR-21 coordinates tumor growth and modulates KRIT1 levels.
- Author
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Orso, Francesca, Balzac, Fiorella, Marino, Marco, Lembo, Antonio, Retta, Saverio Francesco, and Taverna, Daniela
- Subjects
- *
BREAST tumors , *TUMOR growth , *NON-coding RNA , *GENE expression , *ANTINEOPLASTIC agents - Abstract
Highlights: [•] miR-21 targets KRIT1. [•] miR-21 and KRIT1 expression anticorrelate in human breast tumors. [•] KRIT1 is involved in miR-21-mediated tumor cell growth. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
46. Cocrystal structure of the ICAP1 PTB domain in complex with a KRIT1 peptide.
- Author
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Liu, Weizhi and Boggon, Titus J.
- Subjects
- *
INTEGRINS , *AMINO acids , *CELL proliferation , *BONE growth , *ESCHERICHIA coli - Abstract
Integrin cytoplasmic domain-associated protein-1 (ICAP1) is a suppressor of integrin activation and directly binds to the cytoplasmic tail of β1 integrins; its binding suppresses integrin activation by competition with talin. Krev/Rap1 interaction trapped-1 (KRIT1) releases ICAP1 suppression of integrin activation by sequestering ICAP1 away from integrin cytoplasmic tails. Here, the cocrystal structure of the PTB domain of ICAP1 in complex with a 29-amino-acid fragment (residues 170-198) of KRIT1 is presented to 1.7 Å resolution [the resolution at which 〈 I/σ( I)〉 = 2.9 was 1.83 Å]. In previous studies, the structure of ICAP1 with integrin β1 was determined to 3.0 Å resolution and that of ICAP1 with the N-terminal portion of KRIT1 (residues 1-198) was determined to 2.54 Å resolution; therefore, this study provides the highest resolution structure yet of ICAP1 and allows further detailed analysis of the interaction of ICAP1 with its minimal binding region in KRIT1. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
47. CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions.
- Author
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Riant, Florence, Cecillon, Michaelle, Saugier-Veber, Pascale, and Tournier-Lasserve, Elisabeth
- Abstract
Loss of function mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 gene are identified in about 95 % of familial cases of cerebral cavernous malformations and 2/3 of sporadic cases with multiple lesions. In this study, 279 consecutive index patients referred for either genetic counseling or for diagnosis of cerebral hemorrhage of unknown etiology were analyzed for the three cerebral cavernous malformations (CCM) genes by direct sequencing and quantitative studies, to characterize in more detail the mutation spectrum associated with cerebral cavernous malformations and to optimize CCM gene screening. Analysis of the cDNA was performed when possible to detect the consequences of the genomic variations. A pathogenic mutation was identified in 122 patients. CCM1 was mutated in 80 patients (65 %), CCM2 in 23 (19 %), and CCM3 in 19 (16 %). One hundred patients harbored a loss of function point mutation (82 %) and 22 had a large deletion (18 %). Novel unclassified variants were detected in the patients among whom six led to a splicing defect. The causality of three missense variants that did not modify the splicing could not be established. These findings expand the CCM mutation spectrum and highlight the importance of screening the three CCM genes with both direct sequencing and a quantitative method. In addition, six new unclassified variants were shown to be deleterious because they led to a splicing defect. This underlines the necessity of the cDNA analysis when an unknown variant is detected. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
48. Recent insights into cerebral cavernous malformations: the molecular genetics of CCM.
- Author
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Riant, Florence, Bergametti, Francoise, Ayrignac, Xavier, Boulday, Gwenola, and Tournier-Lasserve, Elisabeth
- Subjects
- *
GENETICS , *MOLECULAR biology , *MOLECULAR genetics , *GERM cells , *PROTEINS - Abstract
Cerebral cavernous malformations (CCM) are vascular lesions which can occur as a sporadic (80% of the cases) or familial autosomal dominant form (20%). Three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. Almost 80% of CCM patients affected with a genetic form of the disease harbor a heterozygous germline mutation in one of these three genes. Recent work has shown that a two-hit mechanism is involved in CCM pathogenesis which is caused by a complete loss of any of the three CCM proteins within endothelial cells lining the cavernous capillary cavities. These data were an important step towards the elucidation of the mechanisms of this condition. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
49. Recent insights into cerebral cavernous malformations: animal models of CCM and the human phenotype.
- Author
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Chan, Aubrey C., Li, Dean Y., Berg, Michel J., and Whitehead, Kevin J.
- Subjects
- *
CENTRAL nervous system , *PHENOTYPES , *ANIMAL models in research , *CELL communication , *GENETICS - Abstract
Cerebral cavernous malformations are common vascular lesions of the central nervous system that predispose to seizures, focal neurologic deficits and potentially fatal hemorrhagic stroke. Human genetic studies have identified three genes associated with the disease and biochemical studies of these proteins have identified interaction partners and possible signaling pathways. A variety of animal models of CCM have been described to help translate the cellular and biochemical insights into a better understanding of disease mechanism. In this minireview, we discuss the contributions of animal models to our growing understanding of the biology of cavernous malformations, including the elucidation of the cellular context of CCM protein actions and the in vivo confirmation of abnormal endothelial cell–cell interactions. Challenges and progress towards developing a faithful model of CCM biology are reviewed. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
50. Recent insights into cerebral cavernous malformations: a complex jigsaw puzzle under construction.
- Author
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Faurobert, Eva and Albiges-Rizo, Corinne
- Subjects
- *
CELLS , *GENES , *CELL membranes , *PROTEINS , *NEOVASCULARIZATION - Abstract
Cerebral cavernous malformations (CCM) are common vascular malformations with an unpredictable risk of hemorrhage, the consequences of which range from headache to stroke or death. Three genes, CCM1, CCM2 and CCM3, have been linked to the disease. The encoded CCM proteins interact with each other within a large protein complex. Within the past 2 years, a plethora of new data has emerged on the signaling pathways in which CCM proteins are involved. CCM proteins regulate diverse aspects of endothelial cell morphogenesis and blood vessel stability such as cell–cell junctions, cell shape and polarity, or cell adhesion to the extracellular matrix. Although fascinating, a global picture is hard to depict because little is known about how these pathways coordinate to orchestrate angiogenesis. Here we present what is known about the structural domain organization of CCM proteins, their association as a ternary complex and their subcellular localization. Numerous CCM partners have been identified using two-hybrid screens, genetic analyses or proteomic studies. We focus on the best-characterized partners and review data on the signaling pathways they regulate as a step towards a better understanding of the etiology of CCM disease. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
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