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 V 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.

Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

“…V-ATPase is a multimeric complex composed by a cytosolic domain (v 1 ), responsible for ATP hydrolysis, and a transmembrane domain (v 0 ), responsible for H + transport. Recessive mutations in ATP6V1A, coding for the ''A'' subunit of the v 1 sub-complex, have been first described in patients with cutis laxa, dysmorphic features, and seizures in the context of a severe condition with premature lethality (Van Damme et al, 2017). Subsequently, we described de novo heterozygous mutations in ATP6V1A in four patients with developmental delay and epilepsy with variable of severity, ranging from mild intellectual disability and epilepsy to early-onset epileptic encephalopathies accompanied by myelination defects and brain atrophy.…”

Clinical and molecular characterization of an 18‐month‐old infant with autosomal recessive cutis laxa type 1C due to a novel LTBP4 pathogenic variant, and literature review

“…Urban‐Rifkin‐Davis syndrome, which is due to biallelic variants in the latent transforming growth factor‐beta binding protein 4 gene ( LTBP4 , MIM *604,710) (Callewaert et al, ; Su et al, ; Urban et al, ). ARCL type 2 is separated into ARCL2A (MIM #219200), caused by mutations in the gene encoding for the H + transporting α2 subunit of the vesicular ATPase complex ( ATP6V0A2, MIM *611,716) (Fischer et al, ; Hucthagowder et al, ; Kornak et al, ; Ritelli et al, ), ARCL2B (MIM #612940) that results from mutations in the pyrroline‐5‐carboxylate reductase 1 gene ( PYCR1 ; MIM *179,035) (Dimopoulou et al, ; Reversade et al, ; Ritelli et al, ), and ARCL2C (MIM #612940) and ARCL2D (MIM #617403) that are due to biallelic variants in the ATPase H + transporting V1 subunits E1 ( ATP6V1E1 ; MIM *108,746) and A ( ATP6V1A , MIM *607,027), respectively (Alazami et al, ; Van Damme et al, ). De Barsy syndrome (DBS), previously known as ARCL3A (ARCL3A; MIM #219150), forms a phenotypic continuum with ARCL2 and patients with DBS have been characterized for mutations in the aldehyde dehydrogenase 18 gene ( ALDH18A1 , MIM *138,250) (Guernsey et al, ; Skidmore et al, ) as well as in A TP6V0A2 and PYCR1 (Leao‐Teles, Quelhas, Vilarinho, & Jaeken, ; Zampatti et al, ).…”

“…Different inborn metabolic errors have also been found to be associated with CL (Berk, Bentley, Bayliss, Lind, & Urban, 2012;Gardeitchik & Morava, 2013;Mohamed, Voet, Gardeitchik, & Morava, 2014). The inheritance can be autosomal dominant, autosomal recessive and X-linked recessive, and 13 causative genes have been identified yet (Mohamed et al, 2014;Van Damme et al, 2017).…”

Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

“…Based on its accompanying features, it usually falls within a clinical spectrum that to date includes thirteen delineated conditions corresponding to FBLN5‐, FBLN4‐, ELN‐, ATP6V0A2‐, PYCR1‐, ALDH18A1‐, RIN2‐ , LTBP4 ‐, ATP6V1E1 ‐, and ATP6V1A ‐related cutis laxa, gerodermia osteodysplastica, occipital horn syndrome, and arterial tortuosity syndrome (OMIM 219100, 614437, 130160, 219200, 614438, 219150, 610222, 613177, 108746, 607027, 231070, 304150, 208050) (Callewaert & Urban, 2016; Loeys, De Paepe, & Urban, 2011; Vanakker, Callewaert, Malfait, & Coucke, 2015; Van Damme et al, 2017; Van Maldergem, Dobyns, & Kornak, 2009; Van Maldergem & Loeys, 2009). The underlying molecular defects in CL perturb extracellular matrix assembly and/or homeostasis and involve all steps in elastic fiber formation.…”