Gregory M Enns1, Vandana Shashi2, Matthew Bainbridge3, Michael J Gambello4, Farah R Zahir5, Thomas Bast6, Rebecca Crimian2, Kelly Schoch2, Julia Platt1, Rachel Cox1, Jonathan A Bernstein1, Mena Scavina7, Rhonda S Walter8, Audrey Bibb4, Melanie Jones4, Madhuri Hegde4, Brett H Graham3, Anna C Need9, Angelica Oviedo10, Christian P Schaaf11, Sean Boyle12, Atul J Butte12, Rui Chen13, Rong Chen12, Michael J Clark12, Rajini Haraksingh12, Tina M Cowan14, Ping He15, Sylvie Langlois5, Huda Y Zoghbi16, Michael Snyder12, Richard A Gibbs17, Hudson H Freeze15, David B Goldstein18. 1. Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA. 2. Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA. 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. 4. Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA. 5. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. 6. Epilepsy Centre Kork, Kehl, Germany. 7. Division of Pediatric Neurology, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA. 8. Division of Developmental Medicine, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA. 9. Department of Medicine, Imperial College, London, UK. 10. Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. 11. 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. 12. Department of Genetics, Stanford University, Stanford, California, USA. 13. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA. 14. Department of Pathology, Stanford University, Stanford, California, USA. 15. Sanford-Burnham Medical Research Institute, La Jolla, California, USA. 16. 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA [3] Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA. 17. 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. 18. 1] Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA [2] Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
Abstract
PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.
PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.
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