Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.
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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.
Endoplasmic Reticulum-Associated Degradation
Genome-Wide Association Study
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
Sequence Analysis, DNA
Published Version (Please cite this version)10.1038/gim.2014.22
Publication InfoEnns, Gregory M; Shashi, Vandana; Bainbridge, Matthew; Gambello, Michael J; Zahir, Farah R; Bast, Thomas; ... Goldstein, David B (2014). Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med, 16(10). pp. 751-758. 10.1038/gim.2014.22. Retrieved from https://hdl.handle.net/10161/8406.
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Adjunct Professor in the Department of Molecular Genetics and Microbiology
Professor of Pediatrics
Undiagnosed and rare diseases cause significant emotional and financial distress to patients who suffer from these and their families. Duke is one of seven clinical sites to be part of the NIH Undiagnosed Diseases Network (UDN). As a principal investigator for the Duke UDN site, I am involved in arranging detailed clinical evaluation for children and adults with undiagnosed diseases and in the interpretation of the genome sequencing that is performed as part of the initiative to obtain
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