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Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa.

ABSTRACT: Defects 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 E1 and A subunits, respectively, of the V1 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.

SUBMITTER: Van Damme T 

PROVIDER: S-EPMC5294668 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa.

Van Damme Tim T   Gardeitchik Thatjana T   Mohamed Miski M   Guerrero-Castillo Sergio S   Freisinger Peter P   Guillemyn Brecht B   Kariminejad Ariana A   Dalloyaux Daisy D   van Kraaij Sanne S   Lefeber Dirk J DJ   Syx Delfien D   Steyaert Wouter W   De Rycke Riet R   Hoischen Alexander A   Kamsteeg Erik-Jan EJ   Wong Sunnie Y SY   van Scherpenzeel Monique M   Jamali Payman P   Brandt Ulrich U   Nijtmans Leo L   Korenke G Christoph GC   Chung Brian H Y BHY   Mak Christopher C Y CCY   Hausser Ingrid I   Kornak Uwe U   Fischer-Zirnsak Björn B   Strom Tim M TM   Meitinger Thomas T   Alanay Yasemin Y   Utine Gulen E GE   Leung Peter K C PKC   Ghaderi-Sohi Siavash S   Coucke Paul P   Symoens Sofie S   De Paepe Anne A   Thiel Christian C   Haack Tobias B TB   Malfait Fransiska F   Morava Eva E   Callewaert Bert B   Wevers Ron A RA  

American journal of human genetics 20170105 2

Defects of the V-type proton (H<sup>+</sup>) 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<sub>1</sub> domain of the hetero  ...[more]

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