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Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease., Introduction Iron-sulfur (Fe-S) clusters are ancient and evolutionarily conserved prosthetic groups with unique chemical properties that enable the proteins that contain them (Fe-S proteins) to function in several essential cellular [...]

Byline: Shravan. Venkatraman, Kesavan. Ramasamy, Pradeep. Nair OBJECTIVES: Carbamazepine (CBZ), an anti-seizure drug, is widely prescribed for the management of focal seizures. At a given therapeutic dose, CBZ exhibits marked [...]

Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocytespecific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF., Introduction The healthy heart requires a highly synchronized series of reduction and oxidation (redox) reactions to support the electrical and mechanical demands of beating cardiomyocytes (1). In the aging population, [...]

We aimed to evaluate the genetic variation of poly (ADP-ribose) polymerase-1 (PARP-1) as risk factor in development of Graves' disease (GD) and Graves' ophthalmopathy (GO) among Chinese individuals. Patients with confirmed diagnosis of GD or healthy individuals with no clinical symptoms of hyperthyroiditis were enrolled at the Department of Ophthalmology, Tianjin First Center Hospital, China. Genetic polymorphism was studied in plasma DNA samples of subjects by polymerase chain reaction of restriction fragment length polymorphism to confirm our hypothesis. Cytokine levels were measured routinely on serum samples of subjects by sandwich ELISA technique. Patients with GG genotype (odds ratio (OR) 95% CI = 2.25 (1.35-3.73), p = 0.002) and carriers of G allele (OR = 2.03 (1.23-3.36), p = 0.006) were at high risk of developing ophthalmopathy. Polymorphism of del/ins of nuclear factor-K[kappa]1 gene (NF[kappa]B1) gene (OR = 7.1 (2.88-17.52), p < 0.0001) and PARP-1 C410T polymorphism was found to be associated with GO (p < 0.05). Cytokine level was significantly higher in patients with GD (p < 0.05), but no significant change in cytokines level among GO patients from baseline (p > 0.05). Our study results recommended that polymorphism of PARP-1 gene is more likely responsible for development of GD in Chinese individuals. We also observed that the polymorphism of gene-related del/ins to NF[kappa]B1 in development of GO. Key words: poly (ADP-ribose) polymerase-1, Graves' disease, Graves' ophthalmopathy, cytokine, polymorphism, gene, genetic polymorphism. Resume: Nous visions a evaluer la variation genetique de la poly (ADP-ribose) polymerase-1 (PARP-1) comme facteur de risque de la maladie de Graves (MG) et de l'ophtalmopathie de Graves (OG) chez des Chinois. Nous avons inscrit a l'etude des patients porteurs d'un diagnostic de MG confirme ou des personnes en bonne sante sans symptomes d'hyperthyroidie dans le service d'ophtalmologie du Premier Hopital central de Tianjin, en Chine. Pour confirmer notre hypothese, nous avons etudie le polymorphisme genetique dans des echantillons plasmatiques d'ADN des sujets a l'aide de l'amplification en chaine par polymerase du polymorphisme des sites de restriction. Nous avons mesure de routine les taux de cytokines dans des echantillons de serum des sujets a l'aide de la technique immunoenzymatique en sandwich. Les patients presentant un genotype GG (rapport de cotes (RC) = 2,25 avec IC a 95 % de 1,35 a 3,73, p = 0,002) et les porteurs de l'allele G (RC = 2,03 (1,23 a 3,36), p = 0,006) etaient exposes a un risque eleve de presenter une ophtalmopathie. Nous avons observe que le polymorphisme de type del/ins du gene du facteur nucleaire [kappa]B1 (NF[kappa]B1) (RC = 7,1 (2,88 a 17,52), p < 0,0001) et le polymorphisme C410T du gene de la PARP-1 etaient associes a l'OG (p < 0,05). Les taux de cytokines etaient nettement plus eleves chez les patients atteints de MG (p < 0,05), mais nous n'avons observe aucune variation notable des taux de cytokines chez les patients atteints d'OG depuis le debut de l'etude (p > 0,05). Les resultats de notre etude montrent que le polymorphisme du gene de la PARP-1 est plus susceptible d'etre responsable de l'apparition de la MG chez les Chinois. Nous avons aussi observe que le polymorphisme (del/ins) du gene NF[kappa]B1 est associe a la presentation de l'OG. [Traduit par la Redaction] Mots-cles : poly (ADP-ribose) polymerase-1, maladie de Graves, ophtalmopathie de Graves, cytokine, polymorphisme, gene, polymorphisme genetique., Introduction Graves' disease (GD) is a polygenic multifactorial autoimmune disease that occurs in approximately 3-11 per 1000 people in Chinese populations (Liu et al. 2014a). GD is characterized by thyroid [...]

Byline: Nafiye. Çakar, Orhan. Görükmez Objective: 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is a rare metabolic disease of valine metabolism. Only 22 cases of HIBCH deficiency have been reported in the literature. [...]

Clustered regularly interspaced short palindromic repeat (CRISPR) loci and their associated (Cas) proteins provide adaptive immunity against viral infection in prokaryotes. Upon infection, short phage sequences known as spacers integrate between CRISPR repeats and are transcribed into small RNA molecules that guide the Cas9 nuclease to the viral targets (protospacers). Streptococcus pyogenes Cas9 cleavage of the viral genome requires the presence of a 5'-NGG-3' protospacer adjacent motif (PAM) sequence immediately downstream of the viral target. It is not known whether and how viral sequences flanked by the correct PAM are chosen as new spacers. Here we show that Cas9 selects functional spacers by recognizing their PAM during spacer acquisition. The replacement of cas9 with alleles that lack the PAM recognition motif or recognize an NGGNG PAM eliminated or changed PAM specificity during spaceracquisition, respectively. Cas9 associates with other proteins of the acquisition machinery (Cas1, Cas2 and Csn2), presumably to provide PAM-specificity to this process. These results establish a new function for Cas9 in the genesis of prokaryotic immunological memory., CRISPR loci and Cas proteins provide adaptive immunity to bacteria and archaea against their viruses (1). To adapt to highly dynamic viral populations, CRISPR-Cas loci evolve rapidly, acquiring short phage [...]

Purpose The D allele of the insertion/deletion (I/D) polymorphism of a 287-bp sequence in the angiotensin-converting enzyme (ACE) gene has been associated with an increased activity of this enzyme. Its role in susceptibility to acute respiratory distress syndrome (ARDS) has not been well defined. We hypothesized that ACE I/D genotype in pediatrics is associated with ARDS and plasma levels of angiotensin II. Methods Prospective case-control study in patients under 15 years of age from a mixed Chilean population. Sixty patients with ARDS and 60 controls were included. Association between ACE genotype and ARDS was evaluated as the primary outcome; mortality and severe hypoxemia were examined as secondary outcomes. Plasma angiotensin-II concentration was measured by immunoassay at admission. Results Frequency of ACE I/D genotype was similar in ARDS and control groups (p = 0.18). In the ARDS group, severe hypoxemia was less frequent in D allele carriers (p < 0.05). Plasma angiotensin-II levels were associated with genotype in the ARDS group, but not controls, being higher in D allele carriers (p = 0.016). Conclusion These data do not support the association between ACE I/D genotype and ARDS, although severe hypoxemia was less frequent in D allele carriers. ACE I/D polymorphism modified angiotensin-II levels in pediatric ARDS, but its pathogenic role is not well understood and needs to be addressed in future studies., Author(s): Pablo Cruces [sup.1] [sup.2], Franco Díaz [sup.1] [sup.3] [sup.4], Alonso Puga [sup.5] [sup.6], Benjamín Erranz [sup.2], Alejandro Donoso [sup.1] [sup.3], Cristóbal Carvajal [sup.2], Jan Wilhelm [sup.3] [sup.7], Gabriela M. [...]

Background/Objectives: Hypovitaminosis D is a major public health problem worldwide and unexpectedly more so in sunny countries. Vitamin D receptor (VDR) gene is associated with inter-individual variance in bone mineral density (BMD). Studies assessing the effect of VDR gene polymorphisms on BMD yielded conflicting results. The aim of this study was to assess the relationship between VDR polymorphisms and BMD in the Lebanese, across age groups and genders and to assess the effect of PTH and lean mass and vitamin D levels on such relationship. Subjects/Methods: In total, 203 subjects aged 65-85 years and 336 children aged 10-17 years. Polymorphisms in the VDR gene were assessed with the restriction enzymes BsmI, TaqI and ApaI. Bone mineral content, BMD and lean mass were measured using Dual-Energy X-ray Absorptiometry (DXA). The dominant hand strength was measured in children. Results: Heterozygote genotype was the most frequent in both age groups. There was no difference in the frequency distribution of genotypes between the young and the elderly. No relationship between VDR genotypes and lean mass was found in either age group. Heterozygote boys had the lowest parathormone (PTH) and heterozygote elderly women had the highest BMD at the spine and forearm. Conclusions: In the Lebanese, the relationship between VDR polymorphisms and BMD differs by age. Survival does not seem to differ by VDR genotype. However, further studies are needed to assess the effect of VDR gene polymorphisms on mortality per se and time to mortality, not evaluated in this study. European journal of Clinical Nutrition (2010) 64, 383-391; doi: 10.1038/ejcn.2010.5; published online 10 February 2010 Keywords: bone mineral density; gene polymorphisms; vitamin D; vitamin D receptor; survival, Introduction Hypovitaminosis D is a major public health problem worldwide and unexpectedly more so in sunny countries such as ones in the Middle East (El-Hajj Fuleihan and Vieth, 2007; Lips, [...]

How living systems detect the presence of genotoxic damage embedded in a million-fold excess of undamaged DNA is an unresolved question in biology. Here we have captured and structurally elucidated a base-excision DNA repair enzyme, MutM, at the stage of initial encounter with a damaged nucleobase, 8-oxoguanine (oxoG), nested within a DNA duplex. Three structures of intrahelical oxoG-encounter complexes are compared with sequence-matched structures containing a normal G base in place of an oxoG lesion. Although the protein-DNA interfaces in the matched complexes differ by only two atoms--those that distinguish oxoG from G--their pronounced structural differences indicate that MutM can detect a lesion in DNA even at the earliest stages of encounter. All-atom computer simulations show the pathway by which encounter of the enzyme with the lesion causes extrusion from the DNA duplex, and they elucidate the critical free energy difference between oxoG and G along the extrusion pathway., Damaged nucleobases in DNA, generated spontaneously through the attack of reactive species on the genome, are an important source of carcinogenic mutations (1,2). Lesion-specific DNA glycosylases catalyse removal of most [...]

Author(s): Prasenjit Dey [1, 2]; Joelle Baddour [3]; Florian Muller [4]; Chia Chin Wu [2]; Huamin Wang [5]; Wen-Ting Liao [1]; Zangdao Lan [1]; Alina Chen [1]; Tony Gutschner [2]; [...]

Byline: Keyvan. Moradi, Reza. Alibakhshi, Shohreh. Khatami Background: Defects either in phenylalanine hydroxylase (PheOH) or in the production and recycling of its cofactor (tetrahydrobiopterin [BH4]) are the causes of primary [...]