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

Enns, Gregory M

Shashi, Vandana

Bainbridge, Matthew

Gambello, Michael J

Zahir, Farah R

Bast, Thomas

Crimian, Rebecca

Schoch, Kelly

Platt, Julia

Cox, Rachel

Bernstein, Jonathan A

Scavina, Mena

Walter, Rhonda S

Bibb, Audrey

Jones, Melanie

Hegde, Madhuri

Graham, Brett H

Need, Anna C

Oviedo, Angelica

Schaaf, Christian P

Boyle, Sean

Butte, Atul J

Chen, Rui

Chen, Rong

Clark, Michael J

Haraksingh, Rajini

FORGE Canada Consortium

Cowan, Tina M

He, Ping

Langlois, Sylvie

Zoghbi, Huda Y

Snyder, Michael

Gibbs, Richard A

Freeze, Hudson H

Goldstein, David B

United States

2014-03-25T14:40:11Z

2014-10

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.

http://www.ncbi.nlm.nih.gov/pubmed/24651605

gim201422

1530-0366

https://hdl.handle.net/10161/8406

eng

Elsevier BV

Genet Med

10.1038/gim.2014.22

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

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

Journal article

http://www.ncbi.nlm.nih.gov/pubmed/24651605

751

758

10

Basic Science Departments

Clinical Science Departments

Duke

Duke Center for Human Genome Variation

Duke Clinical Research Institute

Duke Institute for Brain Sciences

Institutes and Centers

Institutes and Provost's Academic Units

Molecular Genetics and Microbiology

Pediatrics

Pediatrics, Medical Genetics

School of Medicine

University Institutes and Centers

Published

16