title: Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors.
abstract: Restrictive dermopathy (RD) is characterized by intrauterine growth retardation, tight and rigid skin with prominent superficial vessels, bone mineralization defects, dysplastic clavicles, arthrogryposis and early neonatal death. In two patients affected with RD, we recently reported two different heterozygous splicing mutations in the LMNA gene, leading to the production and accumulation of truncated Prelamin A. In other patients, a single nucleotide insertion was identified in ZMPSTE24. This variation is located in a homopolymeric repeat of thymines and introduces a premature termination codon. ZMPSTE24 encodes an endoprotease essential for the post-translational cleavage of the Lamin A precursor and the production of mature Lamin A. However, the autosomal recessive inheritance of RD suggested that a further molecular defect was present either in the second ZMPSTE24 allele or in another gene involved in Lamin A processing. Here, we report new findings in RD linked to ZMPSTE24 mutations. Ten RD patients were analyzed including seven from a previous series and three novel patients. All were found to be either homozygous or compound heterozygous for ZMPSTE24 mutations. We report three novel 'null' mutations as well as the recurrent thymine insertion. In all cases, we find a complete absence of both ZMPSTE24 and mature Lamin A associated with Prelamin A accumulation. Thus, RD is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations, most of which lie in a mutation hotspot within exon 9. The accumulation of truncated or normal length Prelamin A is, therefore, a shared pathophysiological feature in recessive and dominant RD. These findings have an important impact on our knowledge of the pathophysiology in Progeria and related disorders and will help direct the development of therapeutic approaches.
authors.affiliation: Inserm U491, Faculté de Médecine de Marseille, Marseille, France.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Navarro
authors.forename: Juan
authors.initials: J
authors.lastname: Cadiñanos
authors.forename: Annachiara
authors.initials: A
authors.lastname: De Sandre-Giovannoli
authors.forename: Rafaëlle
authors.initials: R
authors.lastname: Bernard
authors.forename: Sébastien
authors.initials: S
authors.lastname: Courrier
authors.forename: Irène
authors.initials: I
authors.lastname: Boccaccio
authors.forename: Amandine
authors.initials: A
authors.lastname: Boyer
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Kleijer
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.forename: Fabienne
authors.initials: F
authors.lastname: Giuliano
authors.forename: Frits A
authors.initials: FA
authors.lastname: Beemer
authors.forename: Jose M
authors.initials: JM
authors.lastname: Freije
authors.forename: Pierre
authors.initials: P
authors.lastname: Cau
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Catherine
authors.initials: C
authors.lastname: Badens
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D018388:Codon, Terminator; D017931:DNA Primers; D005808:Genes, Recessive; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D034904:Lamin Type A; D008074:Lipoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008666:Metalloendopeptidases; D045726:Metalloproteases / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011498:Protein Precursors / Q000378:metabolism*; D012871:Skin Diseases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018388:Codon, Terminator; D017931:DNA Primers; D034904:Lamin Type A; D008074:Lipoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D045726:Metalloproteases; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human