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Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa

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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 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.
Keywords
ABNORMAL PROTEIN GLYCOSYLATION, CONNECTIVE-TISSUE DISORDERS, RENAL TUBULAR-ACIDOSIS, VACUOLAR PROTON PUMP, IMAGE-ANALYSIS, CONGENITAL DISORDERS, MISSENSE MUTATIONS, GOLGI HOMEOSTASIS, DEFICIENCY CAUSES, I-TASSER

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Chicago
Van Damme, Tim, Thatjana Gardeitchik, Miski Mohamed, Sergio Guerrero-Castillo, Peter Freisinger, Brecht Guillemyn, Ariana Kariminejad, et al. 2017. “Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-recessive Cutis Laxa.” American Journal of Human Genetics 100 (2): 216–227.
APA
Van Damme, Tim, Gardeitchik, T., Mohamed, M., Guerrero-Castillo, S., Freisinger, P., Guillemyn, B., Kariminejad, A., et al. (2017). Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa. AMERICAN JOURNAL OF HUMAN GENETICS, 100(2), 216–227.
Vancouver
1.
Van Damme T, Gardeitchik T, Mohamed M, Guerrero-Castillo S, Freisinger P, Guillemyn B, et al. Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa. AMERICAN JOURNAL OF HUMAN GENETICS. 2017;100(2):216–27.
MLA
Van Damme, Tim, Thatjana Gardeitchik, Miski Mohamed, et al. “Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-recessive Cutis Laxa.” AMERICAN JOURNAL OF HUMAN GENETICS 100.2 (2017): 216–227. Print.
@article{8509671,
  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 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.},
  author       = {Van Damme, Tim and Gardeitchik, Thatjana and Mohamed, Miski and Guerrero-Castillo, Sergio and Freisinger, Peter and Guillemyn, Brecht and Kariminejad, Ariana and Dalloyaux, Daisy and van Kraaij, Sanne and Lefeber, Dirk J and Syx, Delfien and Steyaert, Wouter and De Rycke, Riet and Hoischen, Alexander and Kamsteeg, Erik-Jan and Wong, Sunnie Y and van Scherpenzeel, Monique and Jamali, Payman and Brandt, Ulrich and Nijtmans, Leo and Korenke, G Christoph and Chung, Brian HY and Mak, Christopher CY and Hausser, Ingrid and Kornak, Uwe and Fischer-Zirnsak, Bj{\"o}rn and Strom, Tim M and Meitinger, Thomas and Alanay, Yasemin and Utine, Gulen E and Leung, Peter KC and Ghaderi-Sohi, Siavash and Coucke, Paul and Symoens, Sofie and De Paepe, Anne and Thiel, Christian and Haack, Tobias B and Malfait, Fransiska and Morava, Eva and Callewaert, Bert and Wevers, Ron A},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {ABNORMAL PROTEIN GLYCOSYLATION,CONNECTIVE-TISSUE DISORDERS,RENAL TUBULAR-ACIDOSIS,VACUOLAR PROTON PUMP,IMAGE-ANALYSIS,CONGENITAL DISORDERS,MISSENSE MUTATIONS,GOLGI HOMEOSTASIS,DEFICIENCY CAUSES,I-TASSER},
  language     = {eng},
  number       = {2},
  pages        = {216--227},
  title        = {Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2016.12.010},
  volume       = {100},
  year         = {2017},
}

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