Abstract
Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.
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Acknowledgements
MW was supported by a grant from the German Network of Muscular Dystrophies (MD-NET, 01GM0302) funded by the German Ministry of Education and Research (BMBF) and an EU grant Euro-Laminopathies contract #018690. PM was supported by the Wellcome Trust (grant number WT087244) and TDN was funded by the National Foundation for Science and Technology Development (NAFOSTED, grant 106.06-2010.62) Vietnam. The support of LTTH by the Joint Graduate Education Program of Deutscher Akademischer Austauschdienst (DAAD, VNM 04/A17) is acknowledged. CLN was supported by ANR (Agence Nationale de la Recherche, grant R08190AS) and subsequently by French Association against Myopathies (AFM, grant AFMNL). We thank Dr Andrée Robaglia-Schlupp, in charge of the Biological Resource Center (CRB) of the Department of Medical Genetics, La Timone Children’s hospital, Marseille, and Cécile Mouradian and Karine Bertaux for excellent technical support.
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Navarro, C., Esteves-Vieira, V., Courrier, S. et al. New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update. Eur J Hum Genet 22, 1002–1011 (2014). https://doi.org/10.1038/ejhg.2013.258
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DOI: https://doi.org/10.1038/ejhg.2013.258
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