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

Gregory M. Enns, Vandana Shashi, Matthew Bainbridge, Michael J. Gambello, Farah R. Zahir, Thomas Bast, Rebecca Crimian, Kelly Schoch, Julia Platt, Rachel Cox, Jonathan A. Bernstein, Mena Scavina, Rhonda S. Walter, Audrey Bibb, Melanie Jones, Madhuri Hegde, Brett H. Graham, Anna C. Need, Angelica Oviedo, Christian P. SchaafSean Boyle, Atul J. Butte, Rong Chen, Michael J. Clark, Rajini Haraksingh, Tina M. Cowan, Ping He, Sylvie Langlois, Huda Y. Zoghbi, Michael Snyder, Richard A. Gibbs, Hudson H. Freeze, David B. Goldstein, FORGE Canada Consortium

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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.

Original languageEnglish
Pages (from-to)751-758
Number of pages8
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Volume16
Issue number10
DOIs
Publication statusPublished - 1 Oct 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Enns, G. M., Shashi, V., Bainbridge, M., Gambello, M. J., Zahir, F. R., Bast, T., Crimian, R., Schoch, K., Platt, J., Cox, R., Bernstein, J. A., Scavina, M., Walter, R. S., Bibb, A., Jones, M., Hegde, M., Graham, B. H., Need, A. C., Oviedo, A., ... FORGE Canada Consortium (2014). Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genetics in medicine : official journal of the American College of Medical Genetics, 16(10), 751-758. https://doi.org/10.1038/gim.2014.22