Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa

Tim Van Damme, Thatjana Gardeitchik, Miski Mohamed, Sergio Guerrero-Castillo, Peter Freisinger, Brecht Guillemyn, Ariana Kariminejad, Daisy Dalloyaux, Sanne van Kraaij, Dirk J. Lefeber, Delfien Syx, Wouter Steyaert, Riet De Rycke, Alexander Hoischen, Erik Jan Kamsteeg, Sunnie Y. Wong, Monique van Scherpenzeel, Payman Jamali, Ulrich Brandt, Leo NijtmansG. Christoph Korenke, Brian H.Y. Chung, Christopher C.Y. Mak, Ingrid Hausser, Uwe Kornak, Björn Fischer-Zirnsak, Tim M. Strom, Thomas Meitinger, Yasemin Alanay, Gulen E. Utine, Peter K.C. Leung, Siavash Ghaderi-Sohi, Paul Coucke, Sofie Symoens, Anne De Paepe, Christian Thiel, Tobias B. Haack, Fransiska Malfait, Eva Morava, Bert Callewaert, Ron A. Wevers

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)216-227
Number of pages12
JournalAmerican journal of human genetics
Volume100
Issue number2
DOIs
StatePublished - Feb 2 2017

Keywords

  • ARCL2
  • ATP6V1A
  • ATP6V1E1
  • CDG
  • Golgi apparatus
  • V-ATPase
  • autosomal recessive
  • cellular trafficking
  • congenital disorder of glycosylation
  • cutis laxa

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa'. Together they form a unique fingerprint.

  • Cite this

    Van Damme, T., Gardeitchik, T., Mohamed, M., Guerrero-Castillo, S., Freisinger, P., Guillemyn, B., Kariminejad, A., Dalloyaux, D., van Kraaij, S., Lefeber, D. J., Syx, D., Steyaert, W., De Rycke, R., Hoischen, A., Kamsteeg, E. J., Wong, S. Y., van Scherpenzeel, M., Jamali, P., Brandt, U., ... Wevers, R. A. (2017). Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa. American journal of human genetics, 100(2), 216-227. https://doi.org/10.1016/j.ajhg.2016.12.010