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New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

Claire L. Navarro 1, 2 Vera Esteves-Vieira 3 Sebastien Courrier 2 Amandine Boyer 4 Thuy Duong Nguyen 5, 6 Le Thi Thanh Huong 5 Peter Meinke 5, 7 Winnie Schröder 5 Valérie Cormier-Daire 8 Yves Sznajer 9 David J Amor 10 Kristina Lagerstedt 11 Martine Biervliet 12 Peter C van den Akker 13 Pierre Cau 2 Patrice Roll 1, 2, 14 Nicolas Lévy 15, 2 Catherine Badens 16, 2, 15 Manfred Wehnert 5 Annachiara de Sandre-Giovannoli 2, 17 
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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Claire L. Navarro, Vera Esteves-Vieira, Sebastien Courrier, Amandine Boyer, Thuy Duong Nguyen, et al.. New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update. European Journal of Human Genetics, Nature Publishing Group, 2013, 22 (8), pp.1002-1011. ⟨10.1038/ejhg.2013.258⟩. ⟨hal-01664301⟩



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