Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa.

Abstract

Several inborn errors of metabolism show cutis laxa as a highly recognizable feature. One group of these metabolic cutis laxa conditions is autosomal recessive cutis laxa type 2 caused by defects in v-ATPase components or the mitochondrial proline cycle. Besides cutis laxa, muscular hypotonia and cardiac abnormalities are hallmarks of autosomal recessive cutis laxa type 2D (ARCL2D) due to pathogenic variants in ATP6V1A encoding subunit A of the v-ATPase. Here, we report on three affected individuals from two families with ARCL2D in whom we performed whole exome and Sanger sequencing. We performed functional studies in fibroblasts from one individual, summarized all known probands' clinical, molecular, and biochemical features and compared them, also to other metabolic forms of cutis laxa. We identified novel missense and the first nonsense variant strongly affecting ATP6V1A expression. All six ARCL2D affected individuals show equally severe cutis laxa and dysmorphism at birth. While for one no information was available, two died in infancy and three are now adolescents with mild or absent intellectual disability. Muscular weakness, ptosis, contractures, and elevated muscle enzymes indicated a persistent myopathy. In cellular studies, a fragmented Golgi compartment, a delayed Brefeldin A-induced retrograde transport and glycosylation abnormalities were present in fibroblasts from two individuals. This is the second and confirmatory report on pathogenic variants in ATP6V1A as the cause of this extremely rare condition and the first to describe a nonsense allele. Our data highlight the tremendous clinical variability of ATP6V1A related phenotypes even within the same family.

• Authors: Guido Vogt, Naji El Choubassi, Ágnes Herczegfalvi, Heike Kölbel, Anja Lekaj, Ulrike Schara, Manuel Holtgrewe, Sabine Krause, Rita Horvath, Markus Schuelke, Christoph Hübner, Stefan Mundlos, Andreas Roos, Hanns Lochmüller, Veronika Karcagi, Uwe Kornak, Björn Fischer-Zirnsak
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 44 Issue 4 Pg. 972-986 (07 2021) ISSN: 1573-2665 [Electronic] United States
• PMID: 33320377 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Chemical References

• ATP6V1A protein, human
• Vacuolar Proton-Translocating ATPases

Topics

• Adolescent
• Alleles
• Case-Control Studies
• Cutis Laxa (genetics)
• Fibroblasts (metabolism)
• Golgi Apparatus (metabolism)
• Humans
• Infant
• Infant, Newborn
• Intellectual Disability (genetics)
• Male
• Mutation, Missense
• Pedigree
• Phenotype
• Vacuolar Proton-Translocating ATPases (genetics)