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Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa.
Am. J. Hum. Genet. 100, 216-227 (2017)
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Arcl2 ; Atp6v1a ; Atp6v1e1 ; Autosomal Recessive ; Cdg ; Cellular Trafficking ; Congenital Disorder Of Glycosylation ; Cutis Laxa ; Golgi Apparatus ; V-atpase; Abnormal Protein Glycosylation; Connective-tissue Disorders; Renal Tubular-acidosis; Vacuolar Proton Pump; Image-analysis; Congenital Disorders; Missense Mutations; Golgi Homeostasis; Deficiency Causes; I-tasser
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 100, Heft: 2, Seiten: 216-227 Artikelnummer: , Supplement: ,
Verlag Elsevier ; Cell Press
Verlagsort New York, NY
Begutachtungsstatus peer-reviewed