{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T16:15:37Z","timestamp":1756311337357,"version":"3.40.5"},"reference-count":32,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FI 2240\/1\u20101"],"award-info":[{"award-number":["FI 2240\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council Canada","doi-asserted-by":"publisher","award":["MR\/N025431\/1"],"award-info":[{"award-number":["MR\/N025431\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["CFI\u2010JELF 38412"],"award-info":[{"award-number":["CFI\u2010JELF 38412"]}],"id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FDN\u2010167281"],"award-info":[{"award-number":["FDN\u2010167281"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["UM1 HG008900"],"award-info":[{"award-number":["UM1 HG008900"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2010ATPase 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 <jats:italic>ATP6V1A<\/jats:italic> encoding subunit A of the v\u2010ATPase. 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 <jats:italic>ATP6V1A<\/jats:italic> 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\u2010induced retrograde transport and glycosylation abnormalities were present in fibroblasts from two individuals. This is the second and confirmatory report on pathogenic variants in <jats:italic>ATP6V1A<\/jats:italic> as the cause of this extremely rare condition and the first to describe a nonsense allele. Our data highlight the tremendous clinical variability of <jats:italic>ATP6V1A<\/jats:italic> related phenotypes even within the same family.<\/jats:p>","DOI":"10.1002\/jimd.12341","type":"journal-article","created":{"date-parts":[[2020,12,20]],"date-time":"2020-12-20T05:15:36Z","timestamp":1608441336000},"page":"972-986","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Expanding the clinical and molecular spectrum of <scp><i>ATP6V1A<\/i><\/scp> related metabolic cutis laxa"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7475-2972","authenticated-orcid":false,"given":"Guido","family":"Vogt","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Medizinische Genetik und Humangenetik, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt Universit\u00e4t zu Berlin, and Berlin Institute of Health  Berlin Germany"},{"name":"Max Planck Institute for Molecular Genetics, RG Development &amp; Disease  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9112-8223","authenticated-orcid":false,"given":"Naji","family":"El Choubassi","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Genetik und Humangenetik, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt Universit\u00e4t zu Berlin, and Berlin Institute of Health  Berlin Germany"},{"name":"Max Planck Institute for Molecular Genetics, RG Development &amp; Disease  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1gnes","family":"Herczegfalvi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Semmelweis Medical University, II. Pediatric Clinic  Budapest Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"K\u00f6lbel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology University Hospital Essen, University Duisburg\u2010Essen  Essen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Lekaj","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Genetik und Humangenetik, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt Universit\u00e4t zu Berlin, and Berlin Institute of Health  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike","family":"Schara","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology University Hospital Essen, University Duisburg\u2010Essen  Essen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3051-1763","authenticated-orcid":false,"given":"Manuel","family":"Holtgrewe","sequence":"additional","affiliation":[{"name":"CUBI \u2013 Core Unit Bioinformatics Berlin Institute of Health  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3141-886X","authenticated-orcid":false,"given":"Sabine","family":"Krause","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Baur\u2010Institute, Department of Neurology Ludwig\u2010Maximilians\u2010University of Munich  Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Cambridge, Cambridge Biomedical Campus  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2824-3891","authenticated-orcid":false,"given":"Markus","family":"Schuelke","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin corporate member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"H\u00fcbner","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin corporate member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9788-3166","authenticated-orcid":false,"given":"Stefan","family":"Mundlos","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Genetik und Humangenetik, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt Universit\u00e4t zu Berlin, and Berlin Institute of Health  Berlin Germany"},{"name":"Max Planck Institute for Molecular Genetics, RG Development &amp; Disease  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology University Hospital Essen, University Duisburg\u2010Essen  Essen Germany"},{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa  Ottawa Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2324-8001","authenticated-orcid":false,"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa  Ottawa Ontario Canada"},{"name":"Division of Neurology, Department of Medicine, The Ottawa Hospital  Ottawa Canada"},{"name":"Brain and Mind Research Institute University of Ottawa  Ottawa Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronika","family":"Karcagi","sequence":"additional","affiliation":[{"name":"NIEH, Department of Molecular Genetics and Diagnostics  Budapest Hungary"},{"name":"Istenhegyi Genetic Diagnostic Centre  Budapest 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Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt Universit\u00e4t zu Berlin, and Berlin Institute of Health  Berlin Germany"},{"name":"Max Planck Institute for Molecular Genetics, RG Development &amp; Disease  Berlin 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of Inherited Metabolic 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