Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa

dc.contributor.authorVan Damme, Tim
dc.contributor.authorGardeitchik, Thatjana
dc.contributor.authorMohamed, Miski
dc.contributor.authorGuerrero-Castillo, Sergio
dc.contributor.authorFreisinger, Peter
dc.contributor.authorGuillemyn, Brecht
dc.contributor.authorKariminejad, Ariana
dc.contributor.authorDalloyaux, Daisy
dc.contributor.authorVan Kraaij, Sanne
dc.contributor.authorLefeber, Dirk J.
dc.contributor.authorSyx, Delfien
dc.contributor.authorSteyaert, Wouter
dc.contributor.authorDe Rycke, Riet
dc.contributor.authorHoischen, Alexander
dc.contributor.authorKamsteeg, Erik-Jan
dc.contributor.authorWong, Sunnie Y.
dc.contributor.authorvan Scherpenzeel, Monique
dc.contributor.authorJamali, Payman
dc.contributor.authorBrandt, Ulrich
dc.contributor.authorNijtmans, Leo
dc.contributor.authorKorenke, G. Christoph
dc.contributor.authorChung, Brian H. Y.
dc.contributor.authorMak, Christopher C. Y.
dc.contributor.authorHausser, Ingrid
dc.contributor.authorKornak, Uwe
dc.contributor.authorFischer-Zirnsak, Bjorn
dc.contributor.authorStrom, Tim M.
dc.contributor.authorMeitinger, Thomas
dc.contributor.authorAlanay, Yasemin
dc.contributor.authorUtine, Gulen E.
dc.contributor.authorLeung, Peter K. C.
dc.contributor.authorGhaderi-Sohi, Siavash
dc.contributor.authorCoucke, Paul
dc.contributor.authorSymoens, Sofie
dc.contributor.authorDe Paepe, Anne
dc.contributor.authorThiel, Christian
dc.contributor.authorHaack, Tobias B.
dc.contributor.authorMalfait, Fransiska
dc.contributor.authorMorava, Eva
dc.contributor.authorCallewaert, Bert
dc.contributor.authorWevers, Ron A.
dc.date.accessioned2023-02-21T12:42:11Z
dc.date.available2023-02-21T12:42:11Z
dc.date.issued2017-01-01
dc.description.abstractDefects of the V-type proton (H+) 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 El and A subunits, respectively, of the V-1 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.
dc.description.issue2
dc.description.issueFEB 2
dc.description.pages216-227
dc.description.volume100
dc.identifier.doi10.1016/j.ajhg.2016.12.010
dc.identifier.urihttps://hdl.handle.net/11443/2792
dc.identifier.urihttp://dx.doi.org/10.1016/j.ajhg.2016.12.010
dc.identifier.wosWOS:000393352000004
dc.publisherCELL PRESS
dc.relation.ispartofAMERICAN JOURNAL OF HUMAN GENETICS
dc.titleMutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa
dc.typeArticle

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