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      Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.

      1 , 2 , 3 , 4 , 5 , 5 , 5 , 6 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 7 , 7 , 8 , 8 , 9 , 3 , 10 , 11 , 12 , 3 , 3 , 13 , 13 , 13 , 13 , 14 , 15 , 16 , 17 , 18 , 3 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26
      Nature genetics
      Springer Nature

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          Abstract

          Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

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          Most cited references29

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          A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells.

          Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts. RTT patients' iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. Copyright © 2010 Elsevier Inc. All rights reserved.
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            Toxic proteins in neurodegenerative disease.

            J. Taylor (2002)
            A broad range of neurodegenerative disorders is characterized by neuronal damage that may be caused by toxic, aggregation-prone proteins. As genes are identified for these disorders and cell culture and animal models are developed, it has become clear that a major effect of mutations in these genes is the abnormal processing and accumulation of misfolded protein in neuronal inclusions and plaques. Increased understanding of the cellular mechanisms for disposal of abnormal proteins and of the effects of toxic protein accumulation on neuronal survival may allow the development of rational, effective treatment for these disorders.
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              • Record: found
              • Abstract: found
              • Article: not found

              Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth.

              Sequencing of gene-coding regions (the exome) is increasingly used for studying human disease, for which copy-number variants (CNVs) are a critical genetic component. However, detecting copy number from exome sequencing is challenging because of the noncontiguous nature of the captured exons. This is compounded by the complex relationship between read depth and copy number; this results from biases in targeted genomic hybridization, sequence factors such as GC content, and batching of samples during collection and sequencing. We present a statistical tool (exome hidden Markov model [XHMM]) that uses principal-component analysis (PCA) to normalize exome read depth and a hidden Markov model (HMM) to discover exon-resolution CNV and genotype variation across samples. We evaluate performance on 90 schizophrenia trios and 1,017 case-control samples. XHMM detects a median of two rare (<1%) CNVs per individual (one deletion and one duplication) and has 79% sensitivity to similarly rare CNVs overlapping three or more exons discovered with microarrays. With sensitivity similar to state-of-the-art methods, XHMM achieves higher specificity by assigning quality metrics to the CNV calls to filter out bad ones, as well as to statistically genotype the discovered CNV in all individuals, yielding a trio call set with Mendelian-inheritance properties highly consistent with expectation. We also show that XHMM breakpoint quality scores enable researchers to explicitly search for novel classes of structural variation. For example, we apply XHMM to extract those CNVs that are highly likely to disrupt (delete or duplicate) only a portion of a gene. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Nat. Genet.
                Nature genetics
                Springer Nature
                1546-1718
                1061-4036
                May 2015
                : 47
                : 5
                Affiliations
                [1 ] 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [3] Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California, USA.
                [2 ] Institut Imagine, INSERM U1163, Hôpital Necker Enfants Malades, Paris, France.
                [3 ] Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
                [4 ] Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.
                [5 ] 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
                [6 ] 1] Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau, Département de Génétique, UF Génétique du Développement, Neuropathologie, Paris, France. [2] Institut de Neurobiologie de la Méditerranée (INMED) INSERM U901, Marseille, France.
                [7 ] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
                [8 ] Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
                [9 ] Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
                [10 ] Pediatric Metabolism, Institute of Child Health, Hacettepe University, Ankara, Turkey.
                [11 ] Tübitak Bilgem Uekae, Gebze/Kocaeli, Turkey.
                [12 ] Wah Medical College, Wah, Pakistan.
                [13 ] Department of Pediatric Neurology, Children's Hospital, Cairo University, Cairo, Egypt.
                [14 ] Pediatric Neurology Department, Faculty of Medicine, Sohag University, Sohag, Egypt.
                [15 ] Mashhad Medical Genetic Counseling Center, Mashhad, Iran.
                [16 ] Medical Genetics Department, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
                [17 ] Division of Child Neurology, Department of Pediatrics, University of Jordan, Amman, Jordan.
                [18 ] Kuwait Medical Genetics Centre, Maternity Hospital, Safat, Kuwait.
                [19 ] Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California, USA.
                [20 ] Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France.
                [21 ] 1] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [2] Génétique Humaine des Maladies Infectieuses, INSERM U1163, Université Paris Descartes, Institut Imagine, Paris, France. [3] St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
                [22 ] Pediatric Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.
                [23 ] 1] Department of Neurosurgery, Yale University, School of Medicine, New Haven, Connecticut, USA. [2] Department of Neurobiology, Yale University, School of Medicine, New Haven, Connecticut, USA. [3] Department of Genetics, Yale University, School of Medicine, New Haven, Connecticut, USA.
                [24 ] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
                [25 ] Reference Center of Inherited Metabolic Diseases, Paris Descartes University, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
                [26 ] 1] Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [3] New York Genome Center, New York, New York, USA.
                Article
                ng.3256 NIHMS669032
                10.1038/ng.3256
                4414867
                25848753
                43d2f3e3-15f7-4f4c-a113-006afca1c887
                History

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