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

Publication ,  Journal Article
Enns, GM; Shashi, V; Bainbridge, M; Gambello, MJ; Zahir, FR; Bast, T; Crimian, R; Schoch, K; Platt, J; Cox, R; Bernstein, JA; Scavina, M ...
Published in: Genet Med
October 2014

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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Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

October 2014

Volume

16

Issue

10

Start / End Page

751 / 758

Location

United States

Related Subject Headings

  • Young Adult
  • Signal Transduction
  • Sequence Analysis, DNA
  • Seizures
  • Retrospective Studies
  • Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
  • Pedigree
  • Mutation
  • Muscle Hypotonia
  • Movement Disorders
 

Citation

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Enns, G. M., Shashi, V., Bainbridge, M., Gambello, M. J., Zahir, F. R., Bast, T., … Goldstein, D. B. (2014). Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med, 16(10), 751–758. https://doi.org/10.1038/gim.2014.22
Enns, Gregory M., Vandana Shashi, Matthew Bainbridge, Michael J. Gambello, Farah R. Zahir, Thomas Bast, Rebecca Crimian, et al. “Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.Genet Med 16, no. 10 (October 2014): 751–58. https://doi.org/10.1038/gim.2014.22.
Enns GM, Shashi V, Bainbridge M, Gambello MJ, Zahir FR, Bast T, et al. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med. 2014 Oct;16(10):751–8.
Enns, Gregory M., et al. “Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.Genet Med, vol. 16, no. 10, Oct. 2014, pp. 751–58. Pubmed, doi:10.1038/gim.2014.22.
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, Clark MJ, Haraksingh R, FORGE Canada Consortium, Cowan TM, He P, Langlois S, Zoghbi HY, Snyder M, Gibbs RA, Freeze HH, Goldstein DB. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med. 2014 Oct;16(10):751–758.

Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

October 2014

Volume

16

Issue

10

Start / End Page

751 / 758

Location

United States

Related Subject Headings

  • Young Adult
  • Signal Transduction
  • Sequence Analysis, DNA
  • Seizures
  • Retrospective Studies
  • Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
  • Pedigree
  • Mutation
  • Muscle Hypotonia
  • Movement Disorders