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

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 ca...

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Autores principales: Vogt, Guido, El Choubassi, Naji, Herczegfalvi, Ágnes, Kölbel, Heike, Lekaj, Anja, Schara, Ulrike, Holtgrewe, Manuel, Krause, Sabine, Horvath, Rita, Schuelke, Markus, Hübner, Christoph, Mundlos, Stefan, Roos, Andreas, Lochmüller, Hanns, Karcagi, Veronika, Kornak, Uwe, Fischer‐Zirnsak, Björn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8638669/
https://www.ncbi.nlm.nih.gov/pubmed/33320377
http://dx.doi.org/10.1002/jimd.12341
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author Vogt, Guido
El Choubassi, Naji
Herczegfalvi, Ágnes
Kölbel, Heike
Lekaj, Anja
Schara, Ulrike
Holtgrewe, Manuel
Krause, Sabine
Horvath, Rita
Schuelke, Markus
Hübner, Christoph
Mundlos, Stefan
Roos, Andreas
Lochmüller, Hanns
Karcagi, Veronika
Kornak, Uwe
Fischer‐Zirnsak, Björn
author_facet Vogt, Guido
El Choubassi, Naji
Herczegfalvi, Ágnes
Kölbel, Heike
Lekaj, Anja
Schara, Ulrike
Holtgrewe, Manuel
Krause, Sabine
Horvath, Rita
Schuelke, Markus
Hübner, Christoph
Mundlos, Stefan
Roos, Andreas
Lochmüller, Hanns
Karcagi, Veronika
Kornak, Uwe
Fischer‐Zirnsak, Björn
author_sort Vogt, Guido
collection PubMed
description 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.
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spelling pubmed-86386692021-12-09 Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa Vogt, Guido El Choubassi, Naji Herczegfalvi, Ágnes Kölbel, Heike Lekaj, Anja Schara, Ulrike Holtgrewe, Manuel Krause, Sabine Horvath, Rita Schuelke, Markus Hübner, Christoph Mundlos, Stefan Roos, Andreas Lochmüller, Hanns Karcagi, Veronika Kornak, Uwe Fischer‐Zirnsak, Björn J Inherit Metab Dis Original Articles 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. John Wiley & Sons, Inc. 2021-02-04 2021-07 /pmc/articles/PMC8638669/ /pubmed/33320377 http://dx.doi.org/10.1002/jimd.12341 Text en © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Vogt, Guido
El Choubassi, Naji
Herczegfalvi, Ágnes
Kölbel, Heike
Lekaj, Anja
Schara, Ulrike
Holtgrewe, Manuel
Krause, Sabine
Horvath, Rita
Schuelke, Markus
Hübner, Christoph
Mundlos, Stefan
Roos, Andreas
Lochmüller, Hanns
Karcagi, Veronika
Kornak, Uwe
Fischer‐Zirnsak, Björn
Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa
title Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa
title_full Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa
title_fullStr Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa
title_full_unstemmed Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa
title_short Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa
title_sort expanding the clinical and molecular spectrum of atp6v1a related metabolic cutis laxa
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8638669/
https://www.ncbi.nlm.nih.gov/pubmed/33320377
http://dx.doi.org/10.1002/jimd.12341
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