Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway - PubMed (original) (raw)

Case Reports

doi: 10.1038/gim.2014.22. Epub 2014 Mar 20.

Vandana Shashi 2, Matthew Bainbridge 3, Michael J Gambello 4, Farah R Zahir 5, Thomas Bast 6, Rebecca Crimian 2, Kelly Schoch 2, Julia Platt 1, Rachel Cox 1, Jonathan A Bernstein 1, Mena Scavina 7, Rhonda S Walter 8, Audrey Bibb 4, Melanie Jones 4, Madhuri Hegde 4, Brett H Graham 3, Anna C Need 9, Angelica Oviedo 10, Christian P Schaaf 11, Sean Boyle 12, Atul J Butte 12, Rui Chen 13, Rong Chen 12, Michael J Clark 12, Rajini Haraksingh 12; FORGE Canada Consortium; Tina M Cowan 14, Ping He 15, Sylvie Langlois 5, Huda Y Zoghbi 16, Michael Snyder 12, Richard A Gibbs 17, Hudson H Freeze 15, David B Goldstein 18

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Case Reports

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

Gregory M Enns et al. Genet Med. 2014 Oct.

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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.

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Conflicts of Interest

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Relative frequency of clinical findings in NGLY1 deficiency.

Figure 2

Figure 2

Pedigrees of NGLY1-deficienct patients.

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