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1. Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

Author

Visvanathan, Abhirami, Saulnier, Olivier, Chen, Chuan, Haldipur, Parthiv, Orisme, Wilda, Delaidelli, Alberto, Shin, Seungmin, Millman, Jake, Bryant, Andrew, Abeysundara, Namal, Wu, Xujia, Hendrikse, Liam, Patil, Vikas, Bashardanesh, Zahedeh, Golser, Joseph, Livingston, Bryn, Nakashima, Takuma, Funakoshi, Yusuke, Ong, Winnie, Rasnitsyn, Alexandra, Aldinger, Kimberly, Richman, Cory, Van Ommeren, Randy, Lee, John, Ly, Michelle, Vladoiu, Maria, Kharas, Kaitlin, Balin, Polina, Erickson, Anders, Fong, Vernon, Zhang, Jiao, Suárez, Raúl, Wang, Hao, Huang, Ning, Pallota, Jonelle, Douglas, Tajana, Haapasalo, Joonas, Razavi, Ferechte, Silvestri, Evelina, Sirbu, Olga, Worme, Samantha, Kameda-Smith, Michelle, Wu, Xiaochong, Daniels, Craig, MichaelRaj, Antony, Bhaduri, Aparna, Schramek, Daniel, Suzuki, Hiromichi, Garzia, Livia, Ahmed, Nabil, Kleinman, Claudia, Stein, Lincoln, Dirks, Peter, Dunham, Christopher, Jabado, Nada, Rich, Jeremy, Li, Wei, Sorensen, Poul, Wechsler-Reya, Robert, Weiss, William, Millen, Kathleen, Ellison, David, Dimitrov, Dimiter, and Taylor, Michael

Subjects
brain development, brain tumor immunotherapy, cancer genomics, group 3 medulloblastoma, perivascular niche, rhombic lip, Humans, Medulloblastoma, Animals, Neoplastic Stem Cells, Mice, Rhombencephalon, Cerebellar Neoplasms, Endothelial Cells, Stem Cell Niche, Stem Cells, Coculture Techniques, Embryonic Structures, Metencephalon
Abstract

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

Published
2024

2. BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations

Author

Peron, Angela, D’Arco, Felice, Aldinger, Kimberly A., Smith-Hicks, Constance, Zweier, Christiane, Gradek, Gyri A., Bradbury, Kimberley, Accogli, Andrea, Andersen, Erica F., Au, Ping Yee Billie, Battini, Roberta, Beleford, Daniah, Bird, Lynne M., Bouman, Arjan, Bruel, Ange-Line, Busk, Øyvind Løvold, Campeau, Philippe M., Capra, Valeria, Carlston, Colleen, Carmichael, Jenny, Chassevent, Anna, Clayton-Smith, Jill, Bamshad, Michael J., Earl, Dawn L., Faivre, Laurence, Philippe, Christophe, Ferreira, Patrick, Graul-Neumann, Luitgard, Green, Mary J., Haffner, Darrah, Haldipur, Parthiv, Hanna, Suhair, Houge, Gunnar, Jones, Wendy D., Kraus, Cornelia, Kristiansen, Birgit Elisabeth, Lespinasse, James, Low, Karen J., Lynch, Sally Ann, Maia, Sofia, Mao, Rong, Kalinauskiene, Ruta, Melver, Catherine, McDonald, Kimberly, Montgomery, Tara, Morleo, Manuela, Motter, Constance, Openshaw, Amanda S., Palumbos, Janice Cox, Parikh, Aditi Shah, Perilla-Young, Yezmin, Powell, Cynthia M., Person, Richard, Desai, Megha, Piard, Juliette, Pfundt, Rolph, Scala, Marcello, Serey-Gaut, Margaux, Shears, Deborah, Slavotinek, Anne, Suri, Mohnish, Turner, Claire, Tvrdik, Tatiana, Weiss, Karin, Wentzensen, Ingrid M., Zollino, Marcella, Hsieh, Tzung-Chien, de Vries, Bert B. A., Guillemot, Francois, Dobyns, William B., Viskochil, David, and Dias, Cristina

Published
2024
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3. A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing

Author

Saulnier, Olivier, Zagozewski, Jamie, Liang, Lisa, Hendrikse, Liam D., Layug, Paul, Gordon, Victor, Aldinger, Kimberly A., Haldipur, Parthiv, Borlase, Stephanie, Coudière-Morrison, Ludivine, Cai, Ting, Martell, Emma, Gonzales, Naomi M., Palidwor, Gareth, Porter, Christopher J., Richard, Stéphane, Sharif, Tanveer, Millen, Kathleen J., Doble, Brad W., Taylor, Michael D., and Werbowetski-Ogilvie, Tamra E.

Published
2024
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4. Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.

Author

Holtz, Alexander, VanCoillie, Rachel, Vansickle, Elizabeth, Carere, Deanna, Withrow, Kara, Torti, Erin, Juusola, Jane, Millan, Francisca, Person, Richard, Guillen Sacoto, Maria, Si, Yue, Wentzensen, Ingrid, Pugh, Jada, Vasileiou, Georgia, Rieger, Melissa, Reis, André, Aldinger, Kimberly, Dobyns, William, Brunet, Theresa, Hoefele, Julia, Wagner, Matias, Haber, Benjamin, Kotzaeridou, Urania, Keren, Boris, Heron, Delphine, Mignot, Cyril, Heide, Solveig, Courtin, Thomas, Buratti, Julien, Murugasen, Serini, Donald, Kirsten, OHeir, Emily, Moody, Shade, Kim, Katherine, Burton, Barbara, Yoon, Grace, Campo, Miguel, Masser-Frye, Diane, Kozenko, Mariya, Parkinson, Christina, Sell, Susan, Gordon, Patricia, Prokop, Jeremy, Karaa, Amel, Bupp, Caleb, Raby, Benjamin, Sherr, Elliott, and Argilli, Emanuela

Subjects
Hedgehog signaling, MYH10, Neurodevelopmental disorder, Nonmuscle myosin, Primary cilia, Actins, Cilia, Hedgehog Proteins, Humans, Myosin Heavy Chains, Neurodevelopmental Disorders, Nonmuscle Myosin Type IIB
Abstract

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. CONCLUSION: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

Published
2022

5. Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Hendrikse, Liam D, Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H, Erickson, Anders W, Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L, Shokouhian, Mohammad, Suárez, Raúl A, Ly, Michelle, Borlase, Stephanie, Scott, David S, Vladoiu, Maria C, Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y, Kumar, Sachin A, Balin, Polina, Visvanathan, Abhirami, Lee, John JY, Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L, Luu, Betty, Bérubé, Pierre, Wang, Yu C, Pfister, Stefan M, Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A, Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J, Kros, Johan M, Zitterbart, Karel, Bailey, Swneke D, Eberhart, Charles G, Rao, Amulya AN, Giannini, Caterina, Olson, James M, Garami, Miklós, Hauser, Peter, Phillips, Joanna J, Ra, Young S, de Torres, Carmen, Mora, Jaume, Li, Kay KW, Ng, Ho-Keung, Poon, Wai S, Pollack, Ian F, López-Aguilar, Enrique, Gillespie, G Yancey, Van Meter, Timothy E, Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S, Van Meir, Erwin G, Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G, Faria, Claudia C, Roussel, Martine F, Boop, Frederick, Chan, Jennifer A, Aldinger, Kimberly A, Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E, and Thompson, Eric M

Subjects
Stem Cell Research, Brain Disorders, Neurosciences, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Cell Differentiation, Cell Lineage, Cerebellar Neoplasms, Cerebellum, Core Binding Factor alpha Subunits, Hedgehog Proteins, Histone Demethylases, Humans, Ki-67 Antigen, Medulloblastoma, Metencephalon, Muscle Proteins, Mutation, Otx Transcription Factors, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, General Science & Technology
Abstract

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Published
2022

6. Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Author

Jeanne, Médéric, Demory, Hélène, Moutal, Aubin, Vuillaume, Marie-Laure, Blesson, Sophie, Thépault, Rose-Anne, Marouillat, Sylviane, Halewa, Judith, Maas, Saskia M, Motazacker, M Mahdi, Mancini, Grazia MS, van Slegtenhorst, Marjon A, Andreou, Avgi, Cox, Helene, Vogt, Julie, Laufman, Jason, Kostandyan, Natella, Babikyan, Davit, Hancarova, Miroslava, Bendova, Sarka, Sedlacek, Zdenek, Aldinger, Kimberly A, Sherr, Elliott H, Argilli, Emanuela, England, Eleina M, Audebert-Bellanger, Séverine, Bonneau, Dominique, Colin, Estelle, Denommé-Pichon, Anne-Sophie, Gilbert-Dussardier, Brigitte, Isidor, Bertrand, Küry, Sébastien, Odent, Sylvie, Redon, Richard, Khanna, Rajesh, Dobyns, William B, Bézieau, Stéphane, Honnorat, Jérôme, Lohkamp, Bernhard, Toutain, Annick, and Laumonnier, Frédéric

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Neurosciences, Brain Disorders, Pediatric, Intellectual and Developmental Disabilities (IDD), Mental Health, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, Adult, Agenesis of Corpus Callosum, Cerebellum, Child, Child, Preschool, Female, Humans, Hydrolases, Intellectual Disability, Male, Microtubule-Associated Proteins, Models, Molecular, Mutation, Missense, Neurodevelopmental Disorders, Tubulin, Young Adult, DPYSL5, brain malformation, corpus callosum agenesis, de novo missense variants, dendrite branching, neurodevelopmental disorder, primary neuronal cultures, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Published
2021

7. Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex.

Author

Werling, Donna M, Pochareddy, Sirisha, Choi, Jinmyung, An, Joon-Yong, Sheppard, Brooke, Peng, Minshi, Li, Zhen, Dastmalchi, Claudia, Santpere, Gabriel, Sousa, André MM, Tebbenkamp, Andrew TN, Kaur, Navjot, Gulden, Forrest O, Breen, Michael S, Liang, Lindsay, Gilson, Michael C, Zhao, Xuefang, Dong, Shan, Klei, Lambertus, Cicek, A Ercument, Buxbaum, Joseph D, Adle-Biassette, Homa, Thomas, Jean-Leon, Aldinger, Kimberly A, O'Day, Diana R, Glass, Ian A, Zaitlen, Noah A, Talkowski, Michael E, Roeder, Kathryn, State, Matthew W, Devlin, Bernie, Sanders, Stephan J, and Sestan, Nenad

Subjects
BrainVar, DLPFC, LOC101926933 RP11-298I3.1 AL132780.1 ENSG00000257285, PsychENCODE, RHEBL1, dorsolateral prefrontal cortex, fetal transition, mTOR, prenatal eQTL, Biochemistry and Cell Biology, Medical Physiology
Abstract

Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both "constant" and "temporal-predominant" eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.

Published
2020

8. Unified rhombic lip origins of group 3 and group 4 medulloblastoma

Author

Smith, Kyle S., Bihannic, Laure, Gudenas, Brian L., Haldipur, Parthiv, Tao, Ran, Gao, Qingsong, Li, Yiran, Aldinger, Kimberly A., Iskusnykh, Igor Y., Chizhikov, Victor V., Scoggins, Matthew, Zhang, Silu, Edwards, Angela, Deng, Mei, Glass, Ian A., Overman, Lynne M., Millman, Jake, Sjoboen, Alexandria H., Hadley, Jennifer, Golser, Joseph, Mankad, Kshitij, Sheppard, Heather, Onar-Thomas, Arzu, Gajjar, Amar, Robinson, Giles W., Hovestadt, Volker, Orr, Brent A., Patay, Zoltán, Millen, Kathleen J., and Northcott, Paul A.

Published
2022
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9. De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.

Author

Kanca, Oguz, Andrews, Jonathan C, Lee, Pei-Tseng, Patel, Chirag, Braddock, Stephen R, Slavotinek, Anne M, Cohen, Julie S, Gubbels, Cynthia S, Aldinger, Kimberly A, Williams, Judy, Indaram, Maanasa, Fatemi, Ali, Yu, Timothy W, Agrawal, Pankaj B, Vezina, Gilbert, Simons, Cas, Crawford, Joanna, Lau, C Christopher, Undiagnosed Diseases Network, Chung, Wendy K, Markello, Thomas C, Dobyns, William B, Adams, David R, Gahl, William A, Wangler, Michael F, Yamamoto, Shinya, Bellen, Hugo J, and Malicdan, May Christine V

Subjects
Undiagnosed Diseases Network, Cerebellum, Animals, Humans, Drosophila melanogaster, Epilepsy, Nervous System Malformations, Coloboma, Microfilament Proteins, Developmental Disabilities, Amino Acid Sequence, Sequence Homology, Phenotype, Mutation, Adult, Child, Infant, Infant, Newborn, Female, Male, Young Adult, Body Dysmorphic Disorders, Intellectual Disability, WD40 Repeats, CG12333, Drosophila, WD40 repeats, WDR37 domains, bang sensitivity, wdr37, Genetics, Pediatric, Rare Diseases, Congenital Structural Anomalies, Neurodegenerative, Neurosciences, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

Published
2019

10. Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development

Author

Williamson, Daniel, Schwalbe, Edward C., Hicks, Debbie, Aldinger, Kimberly A., Lindsey, Janet C., Crosier, Stephen, Richardson, Stacey, Goddard, Jack, Hill, Rebecca M., Castle, Jemma, Grabovska, Yura, Hacking, James, Pizer, Barry, Wharton, Stephen B., Jacques, Thomas S., Joshi, Abhijit, Bailey, Simon, and Clifford, Steven C.

Published
2022
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11. Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

Author

Tripathy, Ratna, Leca, Ines, van Dijk, Tessa, Weiss, Janneke, van Bon, Bregje W, Sergaki, Maria Christina, Gstrein, Thomas, Breuss, Martin, Tian, Guoling, Bahi-Buisson, Nadia, Paciorkowski, Alexander R, Pagnamenta, Alistair T, Wenninger-Weinzierl, Andrea, Martinez-Reza, Maria Fernanda, Landler, Lukas, Lise, Stefano, Taylor, Jenny C, Terrone, Gaetano, Vitiello, Giuseppina, Del Giudice, Ennio, Brunetti-Pierri, Nicola, D’Amico, Alessandra, Reymond, Alexandre, Voisin, Norine, Bernstein, Jonathan A, Farrelly, Ellyn, Kini, Usha, Leonard, Thomas A, Valence, Stéphanie, Burglen, Lydie, Armstrong, Linlea, Hiatt, Susan M, Cooper, Gregory M, Aldinger, Kimberly A, Dobyns, William B, Mirzaa, Ghayda, Pierson, Tyler Mark, Baas, Frank, Chelly, Jamel, Cowan, Nicholas J, and Keays, David Anthony

Subjects
Biomedical and Clinical Sciences, Neurosciences, Rare Diseases, Pediatric, Genetics, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Congenital Structural Anomalies, 2.1 Biological and endogenous factors, Aetiology, Neurological, Agenesis of Corpus Callosum, Animals, Animals, Newborn, Apoptosis, Brain, Cells, Cultured, Cerebellum, Child, Developmental Disabilities, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Humans, Male, Malformations of Cortical Development, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubule-Associated Proteins, Mutation, Nerve Tissue Proteins, Nervous System Malformations, PAX6 Transcription Factor, MAST1, cerebellar hypoplasia, corpus callosum, microdeletion, microtubules, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Published
2018

13. NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain

Author

Liu, Sanxiong, Aldinger, Kimberly A., Cheng, Chi Vicky, Kiyama, Takae, Dave, Mitali, McNamara, Hanna K., Zhao, Wukui, Stafford, James M., Descostes, Nicolas, Lee, Pedro, Caraffi, Stefano G., Ivanovski, Ivan, Errichiello, Edoardo, Zweier, Christiane, Zuffardi, Orsetta, Schneider, Michael, Papavasiliou, Antigone S., Perry, M. Scott, Humberson, Jennifer, Cho, Megan T., Weber, Astrid, Swale, Andrew, Badea, Tudor C., Mao, Chai-An, Garavelli, Livia, Dobyns, William B., and Reinberg, Danny

Published
2021
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14. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Harris, Holly K., Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S., Soucy, Aubrie, Genetti, Casie A., Suslovitch, Victoria, Rodan, Lance H., Tiller, George E., Lesca, Gaetan, Gripp, Karen W., Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D., Turnpenny, Peter D., Simon, Marleen E.H., Volker-Touw, Catharina M.L., Gassen, Koen L.I. van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B.A. de, Immken, LaDonna L., Buchanan, Catherine, Willing, Marcia, Toler, Tomi L., Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Julian L., Jr., Fannemel, Madeleine, Posey, Jennifer E., Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R., Larsen, Martin J., Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K., Walsh, Laurence E., Aldinger, Kimberly A., Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P., Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B., Cohen, Lilian L., Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B., Beggs, Alan H., and Yu, Timothy W.

Published
2021
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15. Correction: Pleiotropic Mechanisms Indicated for Sex Differences in Autism.

Author

Mitra, Ileena, Tsang, Kathryn, Ladd-Acosta, Christine, Croen, Lisa A, Aldinger, Kimberly A, Hendren, Robert L, Traglia, Michela, Lavillaureix, Alinoë, Zaitlen, Noah, Oldham, Michael C, Levitt, Pat, Nelson, Stanley, Amaral, David G, Hertz-Picciotto, Irva, Fallin, M Daniele, and Weiss, Lauren A

Subjects
Developmental Biology, Genetics
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1006425.].

Published
2017

16. Biallelic mutations in the 3′ exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing

Author

Lardelli, Rea M, Schaffer, Ashleigh E, Eggens, Veerle RC, Zaki, Maha S, Grainger, Stephanie, Sathe, Shashank, Van Nostrand, Eric L, Schlachetzki, Zinayida, Rosti, Basak, Akizu, Naiara, Scott, Eric, Silhavy, Jennifer L, Heckman, Laura Dean, Rosti, Rasim Ozgur, Dikoglu, Esra, Gregor, Anne, Guemez-Gamboa, Alicia, Musaev, Damir, Mande, Rohit, Widjaja, Ari, Shaw, Tim L, Markmiller, Sebastian, Marin-Valencia, Isaac, Davies, Justin H, de Meirleir, Linda, Kayserili, Hulya, Altunoglu, Umut, Freckmann, Mary Louise, Warwick, Linda, Chitayat, David, Blaser, Susan, Çağlayan, Ahmet Okay, Bilguvar, Kaya, Per, Huseyin, Fagerberg, Christina, Christesen, Henrik T, Kibaek, Maria, Aldinger, Kimberly A, Manchester, David, Matsumoto, Naomichi, Muramatsu, Kazuhiro, Saitsu, Hirotomo, Shiina, Masaaki, Ogata, Kazuhiro, Foulds, Nicola, Dobyns, William B, Chi, Neil C, Traver, David, Spaccini, Luigina, Bova, Stefania Maria, Gabriel, Stacey B, Gunel, Murat, Valente, Enza Maria, Nassogne, Marie-Cecile, Bennett, Eric J, Yeo, Gene W, Baas, Frank, Lykke-Andersen, Jens, and Gleeson, Joseph G

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Pediatric, Alleles, Animals, Cerebellar Diseases, Exonucleases, Female, Humans, Male, Mice, Mutation, Neurodegenerative Diseases, Nuclear Proteins, RNA, Messenger, RNA, Small Nuclear, Spliceosomes, Zebrafish, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.

Published
2017

17. Evidence of disrupted rhombic lip development in the pathogenesis of Dandy–Walker malformation

Author

Haldipur, Parthiv, Bernardo, Silvia, Aldinger, Kimberly A., Sivakumar, Tarika, Millman, Jake, Sjoboen, Alexandria H., Dang, Derek, Dubocanin, Danilo, Deng, Mei, Timms, Andrew E., Davis, Brian D., Plummer, Jasmine T., Mankad, Kshitij, Oztekin, Ozgur, Manganaro, Lucia, Guimiot, Fabien, Adle-Biassette, Homa, Russo, Rosa, Siebert, Joseph R., Kidron, Debora, Petrilli, Giulia, Roux, Nathalie, Razavi, Ferechte, Glass, Ian A., Di Gioia, Cira, Silvestri, Evelina, and Millen, Kathleen J.

Published
2021
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18. DLG4-related synaptopathy: a new rare brain disorder

Author

Rodríguez-Palmero, Agustí, Boerrigter, Melissa Maria, Gómez-Andrés, David, Aldinger, Kimberly A., Marcos-Alcalde, Íñigo, Popp, Bernt, Everman, David B., Lovgren, Alysia Kern, Arpin, Stephanie, Bahrambeigi, Vahid, Beunders, Gea, Bisgaard, Anne-Marie, Bjerregaard, V.A., Bruel, Ange-Line, Challman, Thomas D., Cogné, Benjamin, Coubes, Christine, de Man, Stella A., Denommé-Pichon, Anne-Sophie, Dye, Thomas J., Elmslie, Frances, Feuk, Lars, García-Miñaúr, Sixto, Gertler, Tracy, Giorgio, Elisa, Gruchy, Nicolas, Haack, Tobias B., Haldeman-Englert, Chad R., Haukanes, Bjørn Ivar, Hoyer, Juliane, Hurst, Anna C.E., Isidor, Bertrand, Soller, Maria Johansson, Kushary, Sulagna, Kvarnung, Malin, Landau, Yuval E., Leppig, Kathleen A., Lindstrand, Anna, Kleinendorst, Lotte, MacKenzie, Alex, Mandrile, Giorgia, Mendelsohn, Bryce A., Moghadasi, Setareh, Morton, Jenny E., Moutton, Sebastien, Müller, Amelie J., O’Leary, Melanie, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Pfundt, Rolph, Pode-Shakked, Ben, Rauch, Anita, Repnikova, Elena, Revah-Politi, Anya, Ross, Meredith J., Ruivenkamp, Claudia A.L., Sarrazin, Elisabeth, Savatt, Juliann M., Schlüter, Agatha, Schönewolf-Greulich, Bitten, Shad, Zohra, Shaw-Smith, Charles, Shieh, Joseph T., Shohat, Motti, Spranger, Stephanie, Thiese, Heidi, Mau-Them, Frederic Tran, van Bon, Bregje, van de Burgt, Ineke, van de Laar, Ingrid M.B.H., van Drie, Esmée, van Haelst, Mieke M., van Ravenswaaij-Arts, Conny M., Verdura, Edgard, Vitobello, Antonio, Waldmüller, Stephan, Whiting, Sharon, Zweier, Christiane, Prada, Carlos E., de Vries, Bert B.A., Dobyns, William B., Reiter, Simone F., Gómez-Puertas, Paulino, Pujol, Aurora, and Tümer, Zeynep

Published
2021
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19. Spatial and cell type transcriptional landscape of human cerebellar development

Author

Aldinger, Kimberly A., Thomson, Zachary, Phelps, Ian G., Haldipur, Parthiv, Deng, Mei, Timms, Andrew E., Hirano, Matthew, Santpere, Gabriel, Roco, Charles, Rosenberg, Alexander B., Lorente-Galdos, Belen, Gulden, Forrest O., O’Day, Diana, Overman, Lynne M., Lisgo, Steven N., Alexandre, Paula, Sestan, Nenad, Doherty, Dan, Dobyns, William B., Seelig, Georg, Glass, Ian A., and Millen, Kathleen J.

Published
2021
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20. Known pathogenic gene variants and new candidates detected in sudden unexpected infant death using whole genome sequencing.

Author

Bard, Angela M., Clark, Lindsay V., Cosgun, Erdal, Aldinger, Kimberly A., Timms, Andrew, Quina, Lely A., Ferres, Juan M. Lavista, Jardine, David, Haas, Elisabeth A., Becker, Tatiana M., Pagan, Chelsea M., Santani, Avni, Martinez, Diego, Barua, Soumitra, McNutt, Zakkary, Nesbitt, Addie, Mitchell, Edwin A., and Ramirez, Jan‐Marino

Abstract

The purpose of this study is to gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Whole Genome Sequencing (WGS) was performed on 144 infants that succumbed to SUID, and 573 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. Variants of interest were identified in 88 genes, in 64.6% of our cohort. Seventy‐three of these have been previously associated with SIDS/SUID/SUDP. Forty‐three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders and in two genes associated with immunological function. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy‐two infants met the triple risk hypothesis criteria. Our study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development

Author

Lennox, Ashley L., Hoye, Mariah L., Jiang, Ruiji, Johnson-Kerner, Bethany L., Suit, Lindsey A., Venkataramanan, Srivats, Sheehan, Charles J., Alsina, Fernando C., Fregeau, Brieana, Aldinger, Kimberly A., Moey, Ching, Lobach, Iryna, Afenjar, Alexandra, Babovic-Vuksanovic, Dusica, Bézieau, Stéphane, Blackburn, Patrick R., Bunt, Jens, Burglen, Lydie, Campeau, Philippe M., Charles, Perrine, Chung, Brian H.Y., Cogné, Benjamin, Curry, Cynthia, D’Agostino, Maria Daniela, Di Donato, Nataliya, Faivre, Laurence, Héron, Delphine, Innes, A. Micheil, Isidor, Bertrand, Keren, Boris, Kimball, Amy, Klee, Eric W., Kuentz, Paul, Küry, Sébastien, Martin-Coignard, Dominique, Mirzaa, Ghayda, Mignot, Cyril, Miyake, Noriko, Matsumoto, Naomichi, Fujita, Atsushi, Nava, Caroline, Nizon, Mathilde, Rodriguez, Diana, Blok, Lot Snijders, Thauvin-Robinet, Christel, Thevenon, Julien, Vincent, Marie, Ziegler, Alban, Dobyns, William, Richards, Linda J., Barkovich, A. James, Floor, Stephen N., Silver, Debra L., and Sherr, Elliott H.

Published
2020
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22. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author

Mirzaa, Ghayda M., Chong, Jessica X., Piton, Amélie, Popp, Bernt, Foss, Kimberly, Guo, Hui, Harripaul, Ricardo, Xia, Kun, Scheck, Joshua, Aldinger, Kimberly A., Sajan, Samin A., Tang, Sha, Bonneau, Dominique, Beck, Anita, White, Janson, Mahida, Sonal, Harris, Jacqueline, Smith-Hicks, Constance, Hoyer, Juliane, Zweier, Christiane, Reis, André, Thiel, Christian T., Jamra, Rami Abou, Zeid, Natasha, Yang, Amy, Farach, Laura S., Walsh, Laurence, Payne, Katelyn, Rohena, Luis, Velinov, Milen, Ziegler, Alban, Schaefer, Elise, Gatinois, Vincent, Geneviève, David, Simon, Marleen E.H., Kohler, Jennefer, Rotenberg, Joshua, Wheeler, Patricia, Larson, Austin, Ernst, Michelle E., Akman, Cigdem I., Westman, Rachel, Blanchet, Patricia, Schillaci, Lori-Anne, Vincent-Delorme, Catherine, Gripp, Karen W., Mattioli, Francesca, Guyader, Gwenaël Le, Gerard, Bénédicte, Mathieu-Dramard, Michèle, Morin, Gilles, Sasanfar, Roksana, Ayub, Muhammad, Vasli, Nasim, Yang, Sandra, Person, Rick, Monaghan, Kristin G., Nickerson, Deborah A., van Binsbergen, Ellen, Enns, Gregory M., Dries, Annika M., Rowe, Leah J., Tsai, Anne C.H., Svihovec, Shayna, Friedman, Jennifer, Agha, Zehra, Qamar, Raheel, Rodan, Lance H., Martinez-Agosto, Julian, Ockeloen, Charlotte W., Vincent, Marie, Sunderland, William James, Bernstein, Jonathan A., Eichler, Evan E., Vincent, John B., and Bamshad, Michael J.

Published
2020
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24. Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum

Author

Haldipur, Parthiv, Aldinger, Kimberly A., Bernardo, Silvia, Deng, Mei, Timms, Andrew E., Overman, Lynne M., Winter, Conrad, Lisgo, Steven N., Razavi, Ferechte, Silvestri, Evelina, Manganaro, Lucia, Adle-Biasette, Homa, Guilmiot, Fabien, Russo, Rosa, Kidron, Debora, Hof, Patrick R., Gerrelli, Dianne, Lindsay, Susan J., Dobyns, William B., Glass, Ian A., Alexandre, Paula, and Millen, Kathleen J.

Published
2019

25. Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Hendrikse, Liam D., Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H., Erickson, Anders W., Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L., Shokouhian, Mohammad, Suárez, Raúl A., Ly, Michelle, Borlase, Stephanie, Scott, David S., Vladoiu, Maria C., Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J. Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y., Kumar, Sachin A., Balin, Polina, Visvanathan, Abhirami, Lee, John J. Y., Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L., Luu, Betty, Bérubé, Pierre, Wang, Yu C., Pfister, Stefan M., Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A., Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J., Kros, Johan M., Zitterbart, Karel, Bailey, Swneke D., Eberhart, Charles G., Rao, Amulya A. N., Giannini, Caterina, Olson, James M., Garami, Miklós, Hauser, Peter, Phillips, Joanna J., Ra, Young S., de Torres, Carmen, Mora, Jaume, Li, Kay K. W., Ng, Ho-Keung, Poon, Wai S., Pollack, Ian F., López-Aguilar, Enrique, Gillespie, G. Yancey, Van Meter, Timothy E., Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C., Cooper, Michael K., Rubin, Joshua B., Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S., Van Meir, Erwin G., Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G., Faria, Claudia C., Roussel, Martine F., Boop, Frederick, Chan, Jennifer A., Aldinger, Kimberly A., Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E., Thompson, Eric M., Ansari, Marc, Garre, Maria L., Chico, Fernando, Eguía, Pilar, Pérezpeña, Mario, Morrissy, A. Sorana, Cavalli, Florence M. G., Wu, Xiaochong, Daniels, Craig, Rich, Jeremy N., Jones, Steven J. M., Moore, Richard A., Marra, Marco A., Huang, Xi, Reimand, Jüri, Sorensen, Poul H., Wechsler-Reya, Robert J., Weiss, William A., Pugh, Trevor J., Garzia, Livia, Kleinman, Claudia L., Stein, Lincoln D., Jabado, Nada, Malkin, David, Ayrault, Olivier, Golden, Jeffrey A., Ellison, David W., Doble, Brad, Ramaswamy, Vijay, Werbowetski-Ogilvie, Tamra E., Suzuki, Hiromichi, Millen, Kathleen J., and Taylor, Michael D.

Published
2022
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26. Redefining the Etiologic Landscape of Cerebellar Malformations

Author

Aldinger, Kimberly A., Timms, Andrew E., Thomson, Zachary, Mirzaa, Ghayda M., Bennett, James T., Rosenberg, Alexander B., Roco, Charles M., Hirano, Matthew, Abidi, Fatima, Haldipur, Parthiv, Cheng, Chi V., Collins, Sarah, Park, Kaylee, Zeiger, Jordan, Overmann, Lynne M., Alkuraya, Fowzan S., Biesecker, Leslie G., Braddock, Stephen R., Cathey, Sara, Cho, Megan T., Chung, Brian H.Y., Everman, David B., Zarate, Yuri A., Jones, Julie R., Schwartz, Charles E., Goldstein, Amy, Hopkin, Robert J., Krantz, Ian D., Ladda, Roger L., Leppig, Kathleen A., McGillivray, Barbara C., Sell, Susan, Wusik, Katherine, Gleeson, Joseph G., Nickerson, Deborah A., Bamshad, Michael J., Gerrelli, Dianne, Lisgo, Steven N., Seelig, Georg, Ishak, Gisele E., Barkovich, A. James, Curry, Cynthia J., Glass, Ian A., Millen, Kathleen J., Doherty, Dan, and Dobyns, William B.

Published
2019
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28. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly

Author

Di Donato, Nataliya, Timms, Andrew E., Aldinger, Kimberly A., Mirzaa, Ghayda M., Bennett, James T., Collins, Sarah, Olds, Carissa, Mei, Davide, Chiari, Sara, Carvill, Gemma, Myers, Candace T., Rivière, Jean-Baptiste, Zaki, Maha S., Gleeson, Joseph G., Rump, Andreas, Conti, Valerio, Parrini, Elena, Ross, M.Elizabeth, Ledbetter, David H., Guerrini, Renzo, and Dobyns, William B.

Published
2018
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29. Cerebellar and posterior fossa malformations in patients with autism‐associated chromosome 22q13 terminal deletion

Author

Aldinger, Kimberly A, Kogan, Jillene, Kimonis, Virginia, Fernandez, Bridget, Horn, Denise, Klopocki, Eva, Chung, Brian, Toutain, Annick, Weksberg, Rosanna, Millen, Kathleen J, Barkovich, A James, and Dobyns, William B

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Clinical Research, Rare Diseases, Pediatric, Neurosciences, Brain Disorders, Congenital Structural Anomalies, Pediatric Research Initiative, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adaptor Proteins, Signal Transducing, Adolescent, Autistic Disorder, Cerebellum, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosome Mapping, Chromosomes, Human, Pair 22, Developmental Disabilities, Genetic Association Studies, Genetic Loci, Genotype, Humans, Image Processing, Computer-Assisted, In Situ Hybridization, Fluorescence, Infant, Mutation, Nerve Tissue Proteins, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, cerebellum, chromosome, deletion, SHANK3, Clinical Sciences, Clinical sciences
Abstract

The 22q13.3 deletion causes a neurodevelopmental syndrome, also known as Phelan-McDermid syndrome (MIM #606232), characterized by developmental delay and severe delay or absence of expressive speech. Two patients with hemizygous chromosome 22q13.3 telomeric deletion were referred to us when brain-imaging studies revealed cerebellar vermis hypoplasia (CBVH). To determine whether developmental abnormalities of the cerebellum are a consistent feature of the 22q13.3 deletion syndrome, we examined brain-imaging studies for 10 unrelated subjects with 22q13 terminal deletion. In seven cases where the availability of DNA and array technology allowed, we mapped deletion boundaries using comparative intensity analysis with single nucleotide polymorphism (SNP) microarrays. Approximate deletion boundaries for three additional cases were derived from clinical or published molecular data. We also examined brain-imaging studies for a patient with an intragenic SHANK3 mutation. We report the first brain-imaging data showing that some patients with 22q13 deletions have severe posterior CBVH, and one individual with a SHANK3 mutation has a normal cerebellum. This genotype-phenotype study suggests that the 22q13 deletion phenotype includes abnormal posterior fossa structures that are unlikely to be attributed to SHANK3 disruption. Other genes in the region, including PLXNB2 and MAPK8IP2, display brain expression patterns and mouse mutant phenotypes critical for proper cerebellar development. Future studies of these genes may elucidate their relationship to 22q13.3 deletion phenotypes.

Published
2013

30. Zac1 plays a key role in the development of specific neuronal subsets in the mouse cerebellum

Author

Chung, Seung-Hyuk, Marzban, Hassan, Aldinger, Kimberly, Dixit, Rajiv, Millen, Kathleen, Schuurmans, Carol, and Hawkes, Richard

Abstract

Abstract Background The cerebellum is composed of a diverse array of neuronal subtypes. Here we have used a candidate approach to identify Zac1, a tumor suppressor gene encoding a zinc finger transcription factor, as a new player in the transcriptional network required for the development of a specific subset of cerebellar nuclei and a population of Golgi cells in the cerebellar cortex. Results We found that Zac1 has a complex expression profile in the developing cerebellum, including in two proliferating progenitor populations; the cerebellar ventricular zone and the external granular layer overlying posterior cerebellar lobules IX and X. Zac1 is also expressed in some postmitotic cerebellar neurons, including a subset of GABAergic interneurons in the medial cerebellar nuclei. Notably, GABAergic interneurons in the cerebellar nuclei are derived from the cerebellar ventricular zone, where Zac1 is also expressed, consistent with a lineage relationship between these two Zac1+ populations. Zac1 is also expressed in a small subset of cells in the posterior vermis, including some neurogranin-immunoreactive (NG+) Golgi cells, which, based on short-term birthdating, are derived from the EGL, where Zac1 is also expressed. However, Zac1+ cells and NG+ Golgi cells in the cerebellar cortex also display unique properties, as they are generated within different, albeit overlapping, time windows. Finally, consistent with the expression profile of Zac1, two conspicuous abnormalities were found in the cerebellum of Zac1 null mice: the medial cerebellar nuclei, and not the others, were significantly reduced in size; and the number of Golgi cells in cerebellar lobule IX was reduced by approximately 60% compared to wild-type littermates. Conclusions The data presented here indicate that the tumor suppressor gene Zac1 is expressed in a complex fashion in the developing cerebellum, including in two dividing progenitor populations and in specific subsets of postmitotic neurons, including Golgi cells and GABAergic neurons in the medial nuclei, which require Zac1 for their differentiation. We thus conclude that Zac1 is a critical regulator of normal cerebellar development, adding a new transcriptional regulator to the growing list of factors involved in generating neuronal diversity in the developing cerebellum.

Published
2011

31. Known pathogenic gene variants and new candidates detected in Sudden Unexpected Infant Death (SUID) using Whole Genome Sequencing (WGS)

Author

Ramirez, Jan Marino, primary, Bard, Angela Michelle, additional, Clark, Lindsay V., additional, Cosgun, Erdal, additional, Aldinger, Kimberly A., additional, Timms, Andrew, additional, Quina, Lely A., additional, Lavista Ferres, Juan M, additional, Jardine, David, additional, Haas, Elisabeth A., additional, Becker, Tatiana M., additional, Pagan, Chelsea M., additional, Santani, Avni, additional, Martinez, Diego, additional, Barua, Soumitra, additional, McNutt, Zakkary, additional, and Nesbitt, Addie, additional

Published
2023
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32. Association and Mutation Analyses of 16p11.2 Autism Candidate Genes

Author

Kumar, Ravinesh A, Marshall, Christian R, Badner, Judith A, Babatz, Timothy D, Mukamel, Zohar, Aldinger, Kimberly A, Sudi, Jyotsna, Brune, Camille W, Goh, Gerald, KaraMohamed, Samer, Sutcliffe, James S, Cook, Edwin H, Geschwind, Daniel H, Dobyns, William B, Scherer, Stephen W, and Christian, Susan L

Subjects
Neurosciences, Clinical Research, Biotechnology, Pediatric, Human Genome, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Genetics, Autism, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Neurological, Animals, Autistic Disorder, Chromosomes, Human, Pair 16, DNA Mutational Analysis, Embryo, Mammalian, Exons, Family Health, Genetic Predisposition to Disease, Genetic Variation, Humans, Membrane Proteins, Mice, Promoter Regions, Genetic, General Science & Technology
Abstract

BackgroundAutism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a approximately 500-700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown.Methodology/principal findingsTo identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings.Conclusions/significanceWe have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.

Published
2009

33. Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish

Author

Van De Weghe, Julie C., Rusterholz, Tamara D.S., Latour, Brooke, Grout, Megan E., Aldinger, Kimberly A., Shaheen, Ranad, Dempsey, Jennifer C., Maddirevula, Sateesh, Cheng, Yong-Han H., Phelps, Ian G., Gesemann, Matthias, Goel, Himanshu, Birk, Ohad S., Alanzi, Talal, Rawashdeh, Rifaat, Khan, Arif O., Bamshad, Michael J., Nickerson, Deborah A., Neuhauss, Stephan C.F., Dobyns, William B., Alkuraya, Fowzan S., Roepman, Ronald, Bachmann-Gagescu, Ruxandra, and Doherty, Dan

Published
2017
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35. Macrocephaly and developmental delay caused by missense variants in RAB5C

Author

Koop, Klaas, primary, Yuan, Weimin, additional, Tessadori, Federico, additional, Rodriguez-Polanco, Wilmer R, additional, Grubbs, Jeremy, additional, Zhang, Bo, additional, Osmond, Matt, additional, Graham, Gail, additional, Sawyer, Sarah, additional, Conboy, Erin, additional, Vetrini, Francesco, additional, Treat, Kayla, additional, Płoski, Rafal, additional, Pienkowski, Victor Murcia, additional, Kłosowska, Anna, additional, Fieg, Elizabeth, additional, Krier, Joel, additional, Mallebranche, Coralie, additional, Alban, Ziegler, additional, Aldinger, Kimberly A, additional, Ritter, Deborah, additional, Macnamara, Ellen, additional, Sullivan, Bonnie, additional, Herriges, John, additional, Alaimo, Joseph T, additional, Helbig, Catherine, additional, Ellis, Colin A, additional, Eyk, Clare, additional, Gecz, Jozef, additional, Farrugia, Daniel, additional, Osei-Owusu, Ikeoluwa, additional, Adès, Lesley, additional, Boogaard, Marie-Jose, additional, Fuchs, Sabine, additional, Bakker, Jeroen, additional, Duran, Karen, additional, Dawson, Zachary D, additional, Lindsey, Anika, additional, Huang, Huiyan, additional, Baldridge, Dustin, additional, Silverman, Gary A, additional, Grant, Barth D, additional, Raizen, David, additional, Network, Undiagnosed Diseases, additional, Haaften, Gijs, additional, Pak, Stephen C, additional, Rehmann, Holger, additional, Schedl, Tim, additional, and van Hasselt, Peter, additional

Published
2023
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36. Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant

Author

Di Donato, Nataliya, Jean, Ying Y., Maga, A. Murat, Krewson, Briana D., Shupp, Alison B., Avrutsky, Maria I., Roy, Achira, Collins, Sarah, Olds, Carissa, Willert, Rebecca A., Czaja, Agnieszka M., Johnson, Rachel, Stover, Jessi A., Gottlieb, Steven, Bartholdi, Deborah, Rauch, Anita, Goldstein, Amy, Boyd-Kyle, Victoria, Aldinger, Kimberly A., Mirzaa, Ghayda M., Nissen, Anke, Brigatti, Karlla W., Puffenberger, Erik G., Millen, Kathleen J., Strauss, Kevin A., Dobyns, William B., Troy, Carol M., and Jinks, Robert N.

Published
2016
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38. Macrocephaly and developmental delay caused by missense variants in RAB5C

Author

Metabole ziekten patientenzorg, Cancer, Genetica Groep Van Haaften, Child Health, Infection & Immunity, Koop, Klaas, Yuan, Weimin, Tessadori, Federico, Rodriguez-Polanco, Wilmer R, Grubbs, Jeremy, Zhang, Bo, Osmond, Matt, Graham, Gail, Sawyer, Sarah, Conboy, Erin, Vetrini, Francesco, Treat, Kayla, Płoski, Rafal, Pienkowski, Victor Murcia, Kłosowska, Anna, Fieg, Elizabeth, Krier, Joel, Mallebranche, Coralie, Alban, Ziegler, Aldinger, Kimberly A, Ritter, Deborah, Macnamara, Ellen, Sullivan, Bonnie, Herriges, John, Alaimo, Joseph T, Helbig, Catherine, Ellis, Colin A, Eyk, Clare, Gecz, Jozef, Farrugia, Daniel, Osei-Owusu, Ikeoluwa, Adès, Lesley, Boogaard, Marie-Jose, Fuchs, Sabine, Bakker, Jeroen, Duran, Karen, Dawson, Zachary D, Lindsey, Anika, Huang, Huiyan, Baldridge, Dustin, Silverman, Gary A, Grant, Barth D, Raizen, David, Network, Undiagnosed Diseases, Haaften, Gijs, Pak, Stephen C, Rehmann, Holger, Schedl, Tim, van Hasselt, Peter, Metabole ziekten patientenzorg, Cancer, Genetica Groep Van Haaften, Child Health, Infection & Immunity, Koop, Klaas, Yuan, Weimin, Tessadori, Federico, Rodriguez-Polanco, Wilmer R, Grubbs, Jeremy, Zhang, Bo, Osmond, Matt, Graham, Gail, Sawyer, Sarah, Conboy, Erin, Vetrini, Francesco, Treat, Kayla, Płoski, Rafal, Pienkowski, Victor Murcia, Kłosowska, Anna, Fieg, Elizabeth, Krier, Joel, Mallebranche, Coralie, Alban, Ziegler, Aldinger, Kimberly A, Ritter, Deborah, Macnamara, Ellen, Sullivan, Bonnie, Herriges, John, Alaimo, Joseph T, Helbig, Catherine, Ellis, Colin A, Eyk, Clare, Gecz, Jozef, Farrugia, Daniel, Osei-Owusu, Ikeoluwa, Adès, Lesley, Boogaard, Marie-Jose, Fuchs, Sabine, Bakker, Jeroen, Duran, Karen, Dawson, Zachary D, Lindsey, Anika, Huang, Huiyan, Baldridge, Dustin, Silverman, Gary A, Grant, Barth D, Raizen, David, Network, Undiagnosed Diseases, Haaften, Gijs, Pak, Stephen C, Rehmann, Holger, Schedl, Tim, and van Hasselt, Peter

Published
2023

46. Medulloblastoma Group 3 and 4 Tumors Comprise a Clinically and Biologically Significant Expression Continuum Reflecting Human Cerebellar Development

Author

Williamson, Daniel, primary, Schwalbe, Edward C, additional, Hicks, Debbie, additional, Aldinger, Kimberly A, additional, Lindsey, Janet C, additional, Crosier, Stephen, additional, Richardson, Stacey, additional, Goddard, Jack, additional, Hill, Rebecca M, additional, Castle, Jemma, additional, Grabovska, Yura, additional, Hacking, James, additional, Pizer, Barry, additional, Wharton, Stephen B, additional, Jacques, Thomas S, additional, Joshi, Abhijit, additional, Bailey, Simon, additional, and Clifford, Steven C, additional

Published
2022
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47. MEDB-78. Unified rhombic lip origins of Group 3 and Group 4 medulloblastoma

Author

Smith, Kyle, primary, Bihannic, Laure, additional, Gudenas, Brian, additional, Gao, Qingsong, additional, Haldipur, Parthiv, additional, Tao, Ran, additional, Iskusnykh, Igor, additional, Chizhikov, Viktor, additional, Scoggins, Matthew, additional, Zhang, Silu, additional, Edwards, Angela, additional, Deng, Mei, additional, Glass, Ian, additional, Overman, Lynne, additional, Millman, Jake, additional, Sjoboen, Alexandria, additional, Hadley, Jennifer, additional, Mankad, Kshitij, additional, Onar-Thomas, Arzu, additional, Gajjar, Amar, additional, Robinson, Giles, additional, Aldinger, Kimberly, additional, Hovestadt, Volker, additional, Tillman, Heather, additional, Orr, Brent, additional, Patay, Zoltán, additional, Millen, Kathleen, additional, and Northcott, Paul, additional

Published
2022
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49. eP098: Exome sequencing of >500 individuals with brain malformation phenotypes reveals marked genetic heterogeneity

Author

Chen, Wei-Liang, primary, Timms, Andrew, additional, Pao, Emily, additional, Chong, Jessica, additional, Bamshad, Michael, additional, Nickerson, Debbie, additional, Doherty, Dan, additional, Novotny, Edward, additional, Saneto, Russell, additional, Ellenbogen, Richard, additional, Hauptman, Jason, additional, Ojemann, Jeff, additional, Dobyns, William, additional, Aldinger, Kimberly, additional, and Mirzaa, Ghayda, additional

Published
2022
Full Text
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