|Title||Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Enns, GM, Shashi, V, Bainbridge, MN, 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, Cowan, TM, He, P, Langlois, S, Zoghbi, HY, Snyder, M, Gibbs, RA, Freeze, HH, Goldstein, DB|
|Date Published||2014 Oct|
|Keywords||Abnormalities, Multiple, Adolescent, 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|
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.
|Alternate Journal||Genet. Med.|
|PubMed Central ID||PMC4243708|
|Grant List||U54-HG003273 / HG / NHGRI NIH HHS / United States |
U54 HD083092 / HD / NICHD NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
T32 HG000044 / HG / NHGRI NIH HHS / United States