title: New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update.
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.
authors.affiliation: 1] Inserm, UMR_S 910, Marseille, France [2] Aix Marseille Université, GMGF, Marseille, France.
authors.forename: Claire Laure
authors.identifier: 0000000194902643
authors.initials: CL
authors.lastname: Navarro
authors.affiliation: Laboratory of Molecular Genetics, Medical Genetics Department, La Timone Children's Hospital, Marseille, France.
authors.forename: Vera
authors.initials: V
authors.lastname: Esteves-Vieira
authors.affiliation: 1] Inserm, UMR_S 910, Marseille, France [2] Aix Marseille Université, GMGF, Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Courrier
authors.affiliation: Laboratory of Molecular Genetics, Medical Genetics Department, La Timone Children's Hospital, Marseille, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Boyer
authors.affiliation: 1] Institute of Human Genetics and Interfaculty Institute of Genetics and Functional Genomics, Department of University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany [2] Institute of Genome Research (IGR), Vietnam Academy of Science and Technology (VAST), Hà Nô˙i, Vietnam.
authors.forename: Thuy
authors.initials: T
authors.lastname: Duong Nguyen
authors.affiliation: 1] Institute of Human Genetics and Interfaculty Institute of Genetics and Functional Genomics, Department of University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany [2] National Institute of Hygiene and Epidemiology, Hà Nô˙i, Vietnam.
authors.forename: Le Thi Thanh
authors.initials: le TT
authors.lastname: Huong
authors.affiliation: Institute of Human Genetics and Interfaculty Institute of Genetics and Functional Genomics, Department of University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Meinke
authors.affiliation: Institute of Human Genetics and Interfaculty Institute of Genetics and Functional Genomics, Department of University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Schröder
authors.affiliation: Inserm/Université U 781, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: Center for Human Genetics, Cliniques Universitaires St-Luc, U.C.L, Bruxelles, Belgique.
authors.forename: Yves
authors.initials: Y
authors.lastname: Sznajer
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.affiliation: Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lagerstedt
authors.affiliation: Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Biervliet
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Peter C
authors.initials: PC
authors.lastname: van den Akker
authors.affiliation: 1] Inserm, UMR_S 910, Marseille, France [2] Aix Marseille Université, GMGF, Marseille, France [3] Laboratory of Cellular Biology, Medical Genetics Department, La Timone Children's Hospital, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cau
authors.affiliation: 1] Inserm, UMR_S 910, Marseille, France [2] Aix Marseille Université, GMGF, Marseille, France [3] Laboratory of Cellular Biology, Medical Genetics Department, La Timone Children's Hospital, Marseille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Roll
authors.affiliation: 1] Inserm, UMR_S 910, Marseille, France [2] Aix Marseille Université, GMGF, Marseille, France [3] Laboratory of Molecular Genetics, Medical Genetics Department, La Timone Children's Hospital, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.affiliation: 1] Inserm, UMR_S 910, Marseille, France [2] Aix Marseille Université, GMGF, Marseille, France [3] Laboratory of Molecular Genetics, Medical Genetics Department, La Timone Children's Hospital, Marseille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Badens
authors.affiliation: Institute of Human Genetics and Interfaculty Institute of Genetics and Functional Genomics, Department of University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wehnert
authors.affiliation: 1] Inserm, UMR_S 910, Marseille, France [2] Aix Marseille Université, GMGF, Marseille, France [3] Laboratory of Molecular Genetics, Medical Genetics Department, La Timone Children's Hospital, Marseille, France.
authors.forename: Annachiara
authors.initials: A
authors.lastname: De Sandre-Giovannoli
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D003286:Contracture / Q000175:diagnosis / Q000235:genetics* / Q000151:congenital; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000235:genetics*; D018703:Founder Effect; D056726:Genetic Association Studies; D006801:Humans; D007438:Introns; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011371:Progeria / Q000175:diagnosis / Q000235:genetics*; D022821:RNA Splice Sites; D012868:Skin Abnormalities / Q000175:diagnosis / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D022821:RNA Splice Sites; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human