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Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

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Date
2014-10
Authors
Enns, Gregory M
Shashi, Vandana
Bainbridge, Matthew
Gambello, Michael J
Zahir, Farah R
Bast, Thomas
Crimian, Rebecca
Schoch, Kelly
Platt, Julia
Cox, Rachel
Bernstein, Jonathan A
Scavina, Mena
Walter, Rhonda S
Bibb, Audrey
Jones, Melanie
Hegde, Madhuri
Graham, Brett H
Need, Anna C
Oviedo, Angelica
Schaaf, Christian P
Boyle, Sean
Butte, Atul J
Chen, Rui
Chen, Rong
Clark, Michael J
Haraksingh, Rajini
FORGE Canada Consortium
Cowan, Tina M
He, Ping
Langlois, Sylvie
Zoghbi, Huda Y
Snyder, Michael
Gibbs, Richard A
Freeze, Hudson H
Goldstein, David B
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(35 total)
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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.
Type
Journal article
Subject
Abnormalities, Multiple
Adolescent
Child, Preschool
Developmental Disabilities
Endoplasmic Reticulum-Associated Degradation
Exome
Family Health
Fatal Outcome
Female
Genome-Wide Association Study
Humans
Infant
Male
Microcephaly
Movement Disorders
Muscle Hypotonia
Mutation
Pedigree
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
Retrospective Studies
Seizures
Sequence Analysis, DNA
Signal Transduction
Young Adult
Permalink
https://hdl.handle.net/10161/8406
Published Version (Please cite this version)
10.1038/gim.2014.22
Publication Info
Enns, 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.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

David Benjamin Goldstein

Adjunct Professor in the Department of Molecular Genetics and Microbiology
Shashi

Vandana Shashi

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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