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Human Molecular Genetics Advance Access published online on April 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi159
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received February 26, 2005
Revised April 11, 2005
Accepted April 11, 2005

Article

Loss of ZMPSTE24 (FACE-1) causes autosomal recessive Restrictive Dermopathy and accumulation of Lamin A precursors

Claire L. Navarro 1, Juan Cadiñanos 2, Annachiara De Sandre-Giovannoli 3, Rafaëlle Bernard 3, Sébastien Courrier 4, Irène Boccaccio 1, Amandine Boyer 3, Wim J. Kleijer 5, Anja Wagner 5, Fabienne Giuliano 6, Frits A. Beemer 7, Jose M. Freije 2, Pierre Cau 1, Raoul C. M. Hennekam 8, Carlos López-Otín 2, Catherine Badens 9, and Nicolas Lévy 10*

1 Inserm U491, Faculté de Médecine de Marseille, Marseille, France
2 Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, Spain
3 Département de Génétique Médicale, Hôpital d'enfants de la Timone, Marseille, France
4 Centre d'Enseignement et de Recherche en Génétique Médicale, Faculté de médecine, Marseille, France
5 Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
6 Service de Génétique Médicale, CHU Nice, Hôpital de l'Archet, Nice, France
7 Clinical Genetics Center, University Medical Center, Utrecht, The Netherlands
8 Department of Pediatrics and Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
9 Département de Génétique Médicale, Hôpital d'enfants de la Timone, Marseille, France; Centre d'Enseignement et de Recherche en Génétique Médicale, Faculté de médecine, Marseille, France
10 Inserm U491, "Génétique Médicale et Développement", Faculté de Médecine de Marseille, 13385 Marseille Cedex 05, France; Département de Génétique Médicale, Hôpital d'enfants de la Timone, Marseille, France; Centre d'Enseignement et de Recherche en Génétique Médicale, Faculté de médecine, Marseille, France

* To whom correspondence should be addressed.
Nicolas Lévy, E-mail: Nicolas.Levy{at}medecine.univ-mrs.fr


  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.


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