Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.
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 articleSubject
Abnormalities, MultipleAdolescent
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
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https://hdl.handle.net/10161/8406Published Version (Please cite this version)
10.1038/gim.2014.22Publication 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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Show full item recordScholars@Duke
David Benjamin Goldstein
Adjunct Professor in the Department of Molecular Genetics and Microbiology
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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