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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Enns, GM; Shashi, V; Bainbridge, M; Gambello, MJ; Zahir, FR; Bast, T; Crimian, R; Schoch, K; Platt, J; Cox, R; Bernstein, JA; Scavina, M; Walter, RS; Bibb, A; Jones, M; Hegde, M; Graham, BH; Need, AC; Oviedo, A; Schaaf, CP; Boyle, S; Butte, AJ; Chen, R; Chen, R; Clark, MJ; Haraksingh, R; FORGE Canada Consortium, ; Cowan, TM; He, P; Langlois, S; Zoghbi, HY; Snyder, M; Gibbs, RA; Freeze, HH; Goldstein, DB

Published Date

  • October 2014

Published In

Volume / Issue

  • 16 / 10

Start / End Page

  • 751 - 758

PubMed ID

  • 24651605

Pubmed Central ID

  • PMC4243708

Electronic International Standard Serial Number (EISSN)

  • 1530-0366

Digital Object Identifier (DOI)

  • 10.1038/gim.2014.22


  • eng

Conference Location

  • United States