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Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2017 Feb 02; Vol. 100 (2), pp. 216-227. Date of Electronic Publication: 2017 Jan 05. - Publication Year :
- 2017
-
Abstract
- Defects of the V-type proton (H <superscript>+</superscript> ) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V <subscript>1</subscript> domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.<br /> (Copyright © 2017 American Society of Human Genetics. All rights reserved.)
- Subjects :
- Adolescent
Alleles
Amino Acid Sequence
Case-Control Studies
Child
Female
Fibroblasts metabolism
Gene Expression Regulation
Genome-Wide Association Study
Glycosylation
Golgi Apparatus metabolism
Humans
Infant
Infant, Newborn
Male
Pedigree
Protein Conformation
Protein Transport
Tandem Mass Spectrometry
Cutis Laxa genetics
Mutation, Missense
Vacuolar Proton-Translocating ATPases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 100
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 28065471
- Full Text :
- https://doi.org/10.1016/j.ajhg.2016.12.010