Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa

  • Am J Hum Genet. 2017 Feb 2;100(2):216-227. doi: 10.1016/j.ajhg.2016.12.010.
Tim Van Damme  1 ,  Thatjana Gardeitchik  2 ,  Miski Mohamed  3 ,  Sergio Guerrero-Castillo  4 ,  Peter Freisinger  5 ,  Brecht Guillemyn  1 ,  Ariana Kariminejad  6 ,  Daisy Dalloyaux  7 ,  Sanne van Kraaij  7 ,  Dirk J Lefeber  8 ,  Delfien Syx  1 ,  Wouter Steyaert  1 ,  Riet De Rycke  9 ,  Alexander Hoischen  10 ,  Erik-Jan Kamsteeg  10 ,  Sunnie Y Wong  11 ,  Monique van Scherpenzeel  8 ,  Payman Jamali  12 ,  Ulrich Brandt  4 ,  Leo Nijtmans  4 ,  G Christoph Korenke  13 ,  Brian H Y Chung  14 ,  Christopher C Y Mak  14 ,  Ingrid Hausser  15 ,  Uwe Kornak  16 ,  Björn Fischer-Zirnsak  16 ,  Tim M Strom  17 ,  Thomas Meitinger  17 ,  Yasemin Alanay  18 ,  Gulen E Utine  19 ,  Peter K C Leung  14 ,  Siavash Ghaderi-Sohi  6 ,  Paul Coucke  1 ,  Sofie Symoens  1 ,  Anne De Paepe  1 ,  Christian Thiel  20 ,  Tobias B Haack  21 ,  Fransiska Malfait  1 ,  Eva Morava  22 ,  Bert Callewaert  23 ,  Ron A Wevers  24
Affiliations
  • 1. Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
  • 2. Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 3. Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 4. Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 5. Childrens' Hospital, Klinikum am Steinenberg, Reutlingen 72764, Germany.
  • 6. Kariminejad-Najmabadi Pathology & Genetics Center, Tehran 14656, Iran.
  • 7. Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 8. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands; Department of Neurology, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 9. Department of Biomedical Molecular Biology, Ghent University, Ghent 9000, Belgium; Inflammation Research Center, VIB, Ghent 9000, Belgium.
  • 10. Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 11. Hayward Genetics Center, Tulane University Medical School, New Orleans, LA 70112, USA.
  • 12. Shahrood Genetic Counseling Center, Semnan 36156, Iran.
  • 13. Department of Neuropediatrics, Children's Hospital Klinikum Oldenburg, Oldenburg 26133, Germany.
  • 14. Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
  • 15. Institute of Pathology, Universitätsklinikum Heidelberg, Heidelberg 69120, Germany.
  • 16. Institute of Medical Genetics and Human Genetics, Charité - Universitaetsmedizin Berlin, Berlin 13353, Germany; Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
  • 17. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
  • 18. Pediatric Genetics Unit, Department of Pediatrics, Acibadem University School of Medicine, Istanbul 34752, Turkey.
  • 19. Pediatric Genetics Unit, Department of Pediatrics, Ihsan Doğramacı Children's Hospital, Hacettepe School of Medicine, Ankara 06100, Turkey.
  • 20. Center for Child and Adolescent Medicine, Klinik Kinderheilkunde I, Universitätsklinikum Heidelberg, Heidelberg 69120, Germany.
  • 21. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany; Institute of Human Genetics, Technische Universität München, Munich 81675, Germany; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72076, Germany.
  • 22. Hayward Genetics Center, Tulane University Medical School, New Orleans, LA 70112, USA; Department of Pediatrics, University Hospital Leuven, Leuven 3000, Belgium.
  • 23. Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium. Electronic address: [email protected].
  • 24. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands. Electronic address: [email protected].
PMID: 28065471 DOI: 10.1016/j.ajhg.2016.12.010
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.

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