title: 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 V1domain 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.
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Van Damme
authors.affiliation: 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.
authors.forename: Thatjana
authors.initials: T
authors.lastname: Gardeitchik
authors.affiliation: Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Miski
authors.initials: M
authors.lastname: Mohamed
authors.affiliation: 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.
authors.forename: Sergio
authors.initials: S
authors.lastname: Guerrero-Castillo
authors.affiliation: Childrens' Hospital, Klinikum am Steinenberg, Reutlingen 72764, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Brecht
authors.initials: B
authors.lastname: Guillemyn
authors.affiliation: Kariminejad-Najmabadi Pathology & Genetics Center, Tehran 14656, Iran.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.affiliation: 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.
authors.forename: Daisy
authors.initials: D
authors.lastname: Dalloyaux
authors.affiliation: 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.
authors.forename: Sanne
authors.initials: S
authors.lastname: van Kraaij
authors.affiliation: 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.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Delfien
authors.initials: D
authors.lastname: Syx
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Steyaert
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent 9000, Belgium; Inflammation Research Center, VIB, Ghent 9000, Belgium.
authors.forename: Riet
authors.initials: R
authors.lastname: De Rycke
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.affiliation: Hayward Genetics Center, Tulane University Medical School, New Orleans, LA 70112, USA.
authors.forename: Sunnie Y
authors.initials: SY
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Monique
authors.initials: M
authors.lastname: van Scherpenzeel
authors.affiliation: Shahrood Genetic Counseling Center, Semnan 36156, Iran.
authors.forename: Payman
authors.initials: P
authors.lastname: Jamali
authors.affiliation: 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.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.affiliation: 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.
authors.forename: Leo
authors.initials: L
authors.lastname: Nijtmans
authors.affiliation: Department of Neuropediatrics, Children's Hospital Klinikum Oldenburg, Oldenburg 26133, Germany.
authors.forename: G Christoph
authors.initials: GC
authors.lastname: Korenke
authors.affiliation: Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Brian H Y
authors.initials: BHY
authors.lastname: Chung
authors.affiliation: Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Christopher C Y
authors.initials: CCY
authors.lastname: Mak
authors.affiliation: Institute of Pathology, Universitätsklinikum Heidelberg, Heidelberg 69120, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.affiliation: Institute of Medical Genetics and Human Genetics, Charité - Universitaetsmedizin Berlin, Berlin 13353, Germany; Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.affiliation: Institute of Medical Genetics and Human Genetics, Charité - Universitaetsmedizin Berlin, Berlin 13353, Germany; Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Fischer-Zirnsak
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Pediatric Genetics Unit, Department of Pediatrics, Acibadem University School of Medicine, Istanbul 34752, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.affiliation: Pediatric Genetics Unit, Department of Pediatrics, Ihsan Doğramacı Children's Hospital, Hacettepe School of Medicine, Ankara 06100, Turkey.
authors.forename: Gulen E
authors.initials: GE
authors.lastname: Utine
authors.affiliation: Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Peter K C
authors.initials: PKC
authors.lastname: Leung
authors.affiliation: Kariminejad-Najmabadi Pathology & Genetics Center, Tehran 14656, Iran.
authors.forename: Siavash
authors.initials: S
authors.lastname: Ghaderi-Sohi
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.affiliation: Center for Child and Adolescent Medicine, Klinik Kinderheilkunde I, Universitätsklinikum Heidelberg, Heidelberg 69120, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.affiliation: 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.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.affiliation: Hayward Genetics Center, Tulane University Medical School, New Orleans, LA 70112, USA; Department of Pediatrics, University Hospital Leuven, Leuven 3000, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium. Electronic address: bert.callewaert@ugent.be.
authors.forename: Bert
authors.initials: B
authors.lastname: Callewaert
authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands. Electronic address: ron.wevers@radboudumc.nl.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
mesh_terms: D000293:Adolescent; D000483:Alleles; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002648:Child; D003483:Cutis Laxa / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D021381:Protein Transport; D053719:Tandem Mass Spectrometry; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
chemical_list: C581697:ATP6V1A protein, human; C462522:ATP6V1E2 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: ARCL2; ATP6V1A; ATP6V1E1; CDG; Golgi apparatus; V-ATPase; autosomal recessive; cellular trafficking; congenital disorder of glycosylation; cutis laxa