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Panneman, D.M.* ; Wortmann, S.B. ; Haaxma, C.A.* ; van Hasselt, P.M.* ; Wolf, N.I.* ; Hendriks, Y.* ; Küsters, B.* ; van Emst-de Vries, S.* ; van de Westerlo, E.* ; Koopman, W.J.H.* ; Wintjes, L.* ; van den Brandt, F.* ; de Vries, M.* ; Lefeber, D.J.* ; Smeitink, J.A.M.* ; Rodenburg, R.J.*

Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.

Clin. Genet. 97, 556-566 (2020)
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NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mitochondrial Disorders ; Ngly1 ; Oxphos Enzyme Activity ; Seahorse Respirometry ; Whole Exome Sequencing; Morphofunction; Diagnosis; Disorder; Disease
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0009-9163
e-ISSN 1399-0004
Journal Clinical Genetics
Quellenangaben Volume: 97, Issue: 4, Pages: 556-566 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
DOI 10.1111/cge.13706
WOS ID WOS:000510163200001
Scopus ID 85081417911
PubMed ID 31957011
Erfassungsdatum 2020-03-17
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