@article {1001, title = {Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 05 07}, pages = {2558}, abstract = {

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.

}, keywords = {Alleles, Amino Acid Sequence, Animals, Child, Preschool, Developmental Disabilities, Drosophila, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Gene Ontology, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Loss of Function Mutation, Male, Muscle Hypotonia, Myoclonic Cerebellar Dyssynergia, Neurodevelopmental Disorders, Neurons, Pedigree, Polymorphism, Single Nucleotide, Ribonucleoproteins, Small Nuclear, Rigor Mortis, RNA-Seq, SMN Complex Proteins}, issn = {2041-1723}, doi = {10.1038/s41467-021-22627-w}, author = {Kour, Sukhleen and Rajan, Deepa S and Fortuna, Tyler R and Anderson, Eric N and Ward, Caroline and Lee, Youngha and Lee, Sangmoon and Shin, Yong Beom and Chae, Jong-Hee and Choi, Murim and Siquier, Karine and Cantagrel, Vincent and Amiel, Jeanne and Stolerman, Elliot S and Barnett, Sarah S and Cousin, Margot A and Castro, Diana and McDonald, Kimberly and Kirmse, Brian and Nemeth, Andrea H and Rajasundaram, Dhivyaa and Innes, A Micheil and Lynch, Danielle and Frosk, Patrick and Collins, Abigail and Gibbons, Melissa and Yang, Michele and Desguerre, Isabelle and Boddaert, Nathalie and Gitiaux, Cyril and Rydning, Siri Lynne and Selmer, Kaja K and Urreizti, Roser and Garcia-Oguiza, Alberto and Osorio, Andr{\'e}s Nascimento and Verdura, Edgard and Pujol, Aurora and McCurry, Hannah R and Landers, John E and Agnihotri, Sameer and Andriescu, E Corina and Moody, Shade B and Phornphutkul, Chanika and Sacoto, Maria J Guillen and Begtrup, Amber and Houlden, Henry and Kirschner, Janbernd and Schorling, David and Rudnik-Sch{\"o}neborn, Sabine and Strom, Tim M and Leiz, Steffen and Juliette, Kali and Richardson, Randal and Yang, Ying and Zhang, Yuehua and Wang, Minghui and Wang, Jia and Wang, Xiaodong and Platzer, Konrad and Donkervoort, Sandra and B{\"o}nnemann, Carsten G and Wagner, Matias and Issa, Mahmoud Y and Elbendary, Hasnaa M and Stanley, Valentina and Maroofian, Reza and Gleeson, Joseph G and Zaki, MAH S and Senderek, Jan and Pandey, Udai Bhan} } @article {830, title = {Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.}, journal = {Cell}, volume = {180}, year = {2020}, month = {2020 02 06}, pages = {568-584.e23}, abstract = {

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n~= 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

}, keywords = {Autistic Disorder, Case-Control Studies, Cell Lineage, Cerebral Cortex, Cohort Studies, Exome, Female, Gene Expression Regulation, Developmental, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Neurobiology, Neurons, Phenotype, Sex Factors, Single-Cell Analysis, Whole Exome Sequencing}, issn = {1097-4172}, doi = {10.1016/j.cell.2019.12.036}, author = {Satterstrom, F Kyle and Kosmicki, Jack A and Wang, Jiebiao and Breen, Michael S and De Rubeis, Silvia and An, Joon-Yong and Peng, Minshi and Collins, Ryan and Grove, Jakob and Klei, Lambertus and Stevens, Christine and Reichert, Jennifer and Mulhern, Maureen S and Artomov, Mykyta and Gerges, Sherif and Sheppard, Brooke and Xu, Xinyi and Bhaduri, Aparna and Norman, Utku and Brand, Harrison and Schwartz, Grace and Nguyen, Rachel and Guerrero, Elizabeth E and Dias, Caroline and Betancur, Catalina and Cook, Edwin H and Gallagher, Louise and Gill, Michael and Sutcliffe, James S and Thurm, Audrey and Zwick, Michael E and B{\o}rglum, Anders D and State, Matthew W and Cicek, A Ercument and Talkowski, Michael E and Cutler, David J and Devlin, Bernie and Sanders, Stephan J and Roeder, Kathryn and Daly, Mark J and Buxbaum, Joseph D} } @article {828, title = {Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism.}, journal = {Proc Natl Acad Sci U S A}, volume = {117}, year = {2020}, month = {2020 05 05}, pages = {10055-10066}, abstract = {

Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit (originally named ). Accordingly, was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking showed corpus callosum hypoplasia, indicating a conserved role for in facilitating neural connectivity. knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of relieved repression of early response genes including AP1 transcription factors (, , , and ), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.

}, keywords = {Actins, Adenosine Triphosphate, Animals, Autism Spectrum Disorder, Behavior, Animal, Chromatin, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, Chromosome Pairing, Corpus Callosum, Dendrites, Disease Models, Animal, DNA-Binding Proteins, Gene Expression Regulation, Hippocampus, Humans, Mice, Mice, Knockout, Mutation, Neurons, Transcription Factors}, issn = {1091-6490}, doi = {10.1073/pnas.1908238117}, author = {Wenderski, Wendy and Wang, Lu and Krokhotin, Andrey and Walsh, Jessica J and Li, Hongjie and Shoji, Hirotaka and Ghosh, Shereen and George, Renee D and Miller, Erik L and Elias, Laura and Gillespie, Mark A and Son, Esther Y and Staahl, Brett T and Baek, Seung Tae and Stanley, Valentina and Moncada, Cynthia and Shipony, Zohar and Linker, Sara B and Marchetto, Maria C N and Gage, Fred H and Chen, Dillon and Sultan, Tipu and Zaki, MAH S and Ranish, Jeffrey A and Miyakawa, Tsuyoshi and Luo, Liqun and Malenka, Robert C and Crabtree, Gerald R and Gleeson, Joseph G} } @article {930, title = {Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.}, journal = {Neuron}, volume = {106}, year = {2020}, month = {2020 04 22}, pages = {246-255.e6}, abstract = {

Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L. We show that CEP85L is required cell autonomously in~vivo and in~vitro for migration, that it localizes to the maternal centriole, and that it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1. Loss of CEP85L disrupts CDK5 localization and activation, leading to centrosome disorganization and disrupted microtubule cytoskeleton organization. Together, our findings suggest that CEP85L highlights a complex that controls CDK5 activity to promote neuronal migration.

}, keywords = {Cell Movement, Centrioles, Child, Child, Preschool, Cyclin-Dependent Kinase 5, Cytoskeletal Proteins, Female, Humans, Lissencephaly, Male, Microtubules, Neocortex, Nerve Tissue Proteins, Neurons, Oncogene Proteins, Fusion, Young Adult}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.01.030}, author = {Kodani, Andrew and Kenny, Connor and Lai, Abbe and Gonzalez, Dilenny M and Stronge, Edward and Sejourne, Gabrielle M and Isacco, Laura and Partlow, Jennifer N and O{\textquoteright}Donnell, Anne and McWalter, Kirsty and Byrne, Alicia B and Barkovich, A James and Yang, Edward and Hill, R Sean and Gawlinski, Pawel and Wiszniewski, Wojciech and Cohen, Julie S and Fatemi, S Ali and Baranano, Kristin W and Sahin, Mustafa and Vossler, David G and Yuskaitis, Christopher J and Walsh, Christopher A} } @article {628, title = {Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.}, journal = {Cell}, volume = {172}, year = {2018}, month = {2018 02 22}, pages = {897-909.e21}, abstract = {

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian~neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly~across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific~transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.

}, keywords = {Alternative Splicing, Alu Elements, Base Sequence, Cohort Studies, CRISPR-Cas Systems, Dystonic Disorders, Family, Female, Genetic Diseases, X-Linked, Genetic Loci, Genome, Human, Haplotypes, High-Throughput Nucleotide Sequencing, Histone Acetyltransferases, Humans, Induced Pluripotent Stem Cells, Introns, Male, Minisatellite Repeats, Models, Genetic, Nerve Degeneration, Neural Stem Cells, Neurons, RNA, Messenger, Short Interspersed Nucleotide Elements, TATA-Binding Protein Associated Factors, Transcription Factor TFIID, Transcriptome}, issn = {1097-4172}, doi = {10.1016/j.cell.2018.02.011}, author = {Aneichyk, Tatsiana and Hendriks, William T and Yadav, Rachita and Shin, David and Gao, Dadi and Vaine, Christine A and Collins, Ryan L and Domingo, Aloysius and Currall, Benjamin and Stortchevoi, Alexei and Multhaupt-Buell, Trisha and Penney, Ellen B and Cruz, Lilian and Dhakal, Jyotsna and Brand, Harrison and Hanscom, Carrie and Antolik, Caroline and Dy, Marisela and Ragavendran, Ashok and Underwood, Jason and Cantsilieris, Stuart and Munson, Katherine M and Eichler, Evan E and Acu{\~n}a, Patrick and Go, Criscely and Jamora, R Dominic G and Rosales, Raymond L and Church, Deanna M and Williams, Stephen R and Garcia, Sarah and Klein, Christine and M{\"u}ller, Ulrich and Wilhelmsen, Kirk C and Timmers, H T Marc and Sapir, Yechiam and Wainger, Brian J and Henderson, Daniel and Ito, Naoto and Weisenfeld, Neil and Jaffe, David and Sharma, Nutan and Breakefield, Xandra O and Ozelius, Laurie J and Bragg, D Cristopher and Talkowski, Michael E} } @article {437, title = {Asprosin is a centrally acting orexigenic hormone.}, journal = {Nat Med}, volume = {23}, year = {2017}, month = {2017 Dec}, pages = {1444-1453}, abstract = {

Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.

}, keywords = {Adolescent, Adult, Animals, Appetite Depressants, Appetite Regulation, Female, Humans, Hypothalamus, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Neurons, Peptide Fragments, Peptide Hormones, Rats, Signal Transduction, Young Adult}, issn = {1546-170X}, doi = {10.1038/nm.4432}, author = {Duerrschmid, Clemens and He, Yanlin and Wang, Chunmei and Li, Chia and Bournat, Juan C and Romere, Chase and Saha, Pradip K and Lee, Mark E and Phillips, Kevin J and Jain, Mahim and Jia, Peilin and Zhao, Zhongming and Farias, Monica and Wu, Qi and Milewicz, Dianna M and Sutton, V Reid and Moore, David D and Butte, Nancy F and Krashes, Michael J and Xu, Yong and Chopra, Atul R} } @article {58, title = {Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 07 01}, pages = {836-845}, abstract = {

IMPORTANCE: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality.

OBJECTIVE: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.

DESIGN, SETTING, AND PARTICIPANTS: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children{\textquoteright}s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.

RESULTS: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.

CONCLUSIONS AND RELEVANCE: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.

}, keywords = {Adolescent, Adult, Amino Acids, Animals, Cells, Cultured, Cerebral Cortex, Child, Child, Preschool, Developmental Disabilities, Embryo, Mammalian, Female, Gene Expression Regulation, Genetic Association Studies, Humans, Intercellular Signaling Peptides and Proteins, Male, Malformations of Cortical Development, Mechanistic Target of Rapamycin Complex 1, Megalencephaly, Mosaicism, Multiprotein Complexes, Mutation, Nerve Tissue Proteins, Neurons, Rats, Retrospective Studies, TOR Serine-Threonine Kinases, Young Adult}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2016.0363}, author = {Mirzaa, Ghayda M and Campbell, Catarina D and Solovieff, Nadia and Goold, Carleton and Jansen, Laura A and Menon, Suchithra and Timms, Andrew E and Conti, Valerio and Biag, Jonathan D and Adams, Carissa and Boyle, Evan August and Collins, Sarah and Ishak, Gisele and Poliachik, Sandra and Girisha, Katta M and Yeung, Kit San and Chung, Brian Hon Yin and Rahikkala, Elisa and Gunter, Sonya A and McDaniel, Sharon S and Macmurdo, Colleen Forsyth and Bernstein, Jonathan A and Martin, Beth and Leary, Rebecca and Mahan, Scott and Liu, Shanming and Weaver, Molly and Doerschner, Michael and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Shendure, Jay and Saneto, Russell P and Novotny, Edward J and Wilson, Christopher J and Sellers, William R and Morrissey, Michael and Hevner, Robert F and Ojemann, Jeffrey G and Guerrini, Renzo and Murphy, Leon O and Winckler, Wendy and Dobyns, William B} } @article {14, title = {Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Nov 03}, pages = {1181-1189}, abstract = {

Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.

}, keywords = {Alleles, Amino Acid Sequence, Basement Membrane, Brain, Carrier Proteins, Cerebellum, Cobblestone Lissencephaly, Developmental Disabilities, Dystroglycans, Eye Abnormalities, Female, Humans, Infant, Male, Membrane Proteins, Mutation, Nervous System Malformations, Neuroglia, Neurons, Pedigree, Phenotype}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.007}, author = {Jerber, Julie and Zaki, Maha S and Al-Aama, Jumana Y and Rosti, Rasim Ozgur and Ben-Omran, Tawfeg and Dikoglu, Esra and Silhavy, Jennifer L and Caglar, Caner and Musaev, Damir and Albrecht, Beate and Campbell, Kevin P and Willer, Tobias and Almuriekhi, Mariam and {\c C}a{\u g}layan, Ahmet Okay and Vajsar, Jiri and Bilguvar, Kaya and Ogur, Gonul and Abou Jamra, Rami and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {21, title = {Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {831-845}, abstract = {

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

}, keywords = {Adenosine Triphosphatases, Adult, Alleles, Animals, ATPases Associated with Diverse Cellular Activities, Axons, Cardiomyopathies, Child, Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Drosophila melanogaster, Female, Fibroblasts, Homozygote, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Muscle Hypotonia, Muscles, Mutation, Nervous System Diseases, Neurons, Optic Atrophy, Phenotype, Polymorphism, Single Nucleotide, Syndrome, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.007}, author = {Harel, Tamar and Yoon, Wan Hee and Garone, Caterina and Gu, Shen and Coban-Akdemir, Zeynep and Eldomery, Mohammad K and Posey, Jennifer E and Jhangiani, Shalini N and Rosenfeld, Jill A and Cho, Megan T and Fox, Stephanie and Withers, Marjorie and Brooks, Stephanie M and Chiang, Theodore and Duraine, Lita and Erdin, Serkan and Yuan, Bo and Shao, Yunru and Moussallem, Elie and Lamperti, Costanza and Donati, Maria A and Smith, Joshua D and McLaughlin, Heather M and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Pippucci, Tommaso and Magini, Pamela and Seri, Marco and Zeviani, Massimo and Hirano, Michio and Hunter, Jill V and Srour, Myriam and Zanigni, Stefano and Lewis, Richard Alan and Muzny, Donna M and Lotze, Timothy E and Boerwinkle, Eric and Gibbs, Richard A and Hickey, Scott E and Graham, Brett H and Yang, Yaping and Buhas, Daniela and Martin, Donna M and Potocki, Lorraine and Graziano, Claudio and Bellen, Hugo J and Lupski, James R} } @article {268, title = {Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.}, journal = {Science}, volume = {343}, year = {2014}, month = {2014 Jan 31}, pages = {506-511}, abstract = {

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

}, keywords = {Animals, Axons, Biological Transport, Cohort Studies, Exome, Gene Regulatory Networks, Genetic Association Studies, Humans, Motor Neuron Disease, Mutation, Neurons, Nucleotides, Pyramidal Tracts, Sequence Analysis, DNA, Spastic Paraplegia, Hereditary, Synapses, Transcriptome, Zebrafish}, issn = {1095-9203}, doi = {10.1126/science.1247363}, author = {Novarino, Gaia and Fenstermaker, Ali G and Zaki, Maha S and Hofree, Matan and Silhavy, Jennifer L and Heiberg, Andrew D and Abdellateef, Mostafa and Rosti, Basak and Scott, Eric and Mansour, Lobna and Masri, Amira and Kayserili, H{\"u}lya and Al-Aama, Jumana Y and Abdel-Salam, Ghada M H and Karminejad, Ariana and Kara, Majdi and Kara, Bulent and Bozorgmehri, Bita and Ben-Omran, Tawfeg and Mojahedi, Faezeh and El Din Mahmoud, Iman Gamal and Bouslam, Naima and Bouhouche, Ahmed and Benomar, Ali and Hanein, Sylvain and Raymond, Laure and Forlani, Sylvie and Mascaro, Massimo and Selim, Laila and Shehata, Nabil and Al-Allawi, Nasir and Bindu, P S and Azam, Matloob and G{\"u}nel, Murat and Caglayan, Ahmet and Bilguvar, Kaya and Tolun, Aslihan and Issa, Mahmoud Y and Schroth, Jana and Spencer, Emily G and Rosti, Rasim O and Akizu, Naiara and Vaux, Keith K and Johansen, Anide and Koh, Alice A and Megahed, Hisham and Durr, Alexandra and Brice, Alexis and Stevanin, Giovanni and Gabriel, Stacy B and Ideker, Trey and Gleeson, Joseph G} } @article {309, title = {Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Mar 07}, pages = {468-74}, abstract = {

Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.

}, keywords = {Basement Membrane, Brain, Cerebellum, Cerebral Cortex, Encephalocele, Female, Genetic Predisposition to Disease, Homozygote, Humans, Laminin, Male, Muscular Dystrophies, Nervous System Malformations, Neuroglia, Neurons, Sequence Deletion, Walker-Warburg Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.02.005}, author = {Radmanesh, Farid and {\c C}a{\u g}layan, Ahmet Okay and Silhavy, Jennifer L and Yilmaz, Cahide and Cantagrel, Vincent and Omar, Tarek and Rosti, Basak and Kaymak{\c c}alan, Hande and Gabriel, Stacey and Li, Mingfeng and {\v S}estan, Nenad and Bilguvar, Kaya and Dobyns, William B and Zaki, Maha S and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {311, title = {Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {2013 Feb 26}, pages = {3489-94}, abstract = {

Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.

}, keywords = {Adult, Age of Onset, Amino Acid Sequence, Base Sequence, Child, Preschool, Exome, Female, Genes, Recessive, Homozygote, Humans, Hydrolysis, Male, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Nerve Degeneration, Neurons, Pedigree, Protein Binding, Sequence Analysis, DNA, Substrate Specificity, Syndrome, Thermodynamics, Ubiquitin, Ubiquitin Thiolesterase}, issn = {1091-6490}, doi = {10.1073/pnas.1222732110}, author = {Bilguvar, Kaya and Tyagi, Navneet K and Ozkara, Cigdem and Tuysuz, Beyhan and Bakircioglu, Mehmet and Choi, Murim and Delil, Sakir and {\c C}a{\u g}layan, Ahmet O and Baranoski, Jacob F and Erturk, Ozdem and Yalcinkaya, Cengiz and Karacorlu, Murat and Dincer, Alp and Johnson, Michele H and Mane, Shrikant and Chandra, Sreeganga S and Louvi, Angeliki and Boggon, Titus J and Lifton, Richard P and Horwich, Arthur L and G{\"u}nel, Murat} }