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Human Molecular Genetics Advance Access originally published online on August 18, 2004
Human Molecular Genetics 2004 13(20):2493-2503; doi:10.1093/hmg/ddh265
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Human Molecular Genetics, Vol. 13, No. 20 © Oxford University Press 2004; all rights reserved

Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy

Claire L. Navarro1,{dagger}, Annachiara De Sandre-Giovannoli1,2,{dagger}, Rafaëlle Bernard1,2,{dagger}, Irène Boccaccio1, Amandine Boyer2, David Geneviève4, Smail Hadj-Rabia5, Caroline Gaudy-Marqueste2, Henk Sillevis Smitt6, Pierre Vabres8, Laurence Faivre9, Alain Verloes11, Ton Van Essen12, Elisabeth Flori13, Raoul Hennekam7, Frits A. Beemer14, Nicole Laurent10, Martine Le Merrer4, Pierre Cau1,3 and Nicolas Lévy1,2,*

1Inserm U491, Génétique Médicale et Développement, Faculté de Médecine de Marseille, 2Département de Génétique Médicale, Hôpital d'enfants de la Timone, Marseille, France, 3Laboratoire de Biologie Cellulaire, Hôpital Conception, Institut Fédératif de Physiopathologie Humaine de Marseille, IFR 125, Marseille, France, 4Inserm U393 and 5Service de dermatologie pédiatrique, Hôpital Necker enfants malades, Paris, France, 6Department of Dermatology and 7Department of Pediatrics and Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands, 8Service de Dermatologie, CHU Poitiers, France, 9Centre de Génétique and 10Service d'Anatomie-Pathologique, CHU de Dijon, France, 11Service de Génétique, Hôpital Robert Debré, Paris, France, 12Department of Clinical Genetics, University Hospital, Groningen, The Netherlands, 13Service de Cytogénétique, Hôpital de Hautepierre, Strasbourg, France and 14Clinical Genetics Center, University Medical Center, Utrecht, The Netherlands

Received July 5, 2004; Revised July 27, 2004; Accepted August 4, 2004

Restrictive dermopathy (RD), also called tight skin contracture syndrome (OMIM 275210), is a rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. We explored nine fetuses/newborns children with RD. Two were found to have an heterozygous splicing mutation in the LMNA gene, leading to the complete or partial loss of exon 11 in mRNAs encoding Lamin A and resulting in a truncated Prelamin A protein. Lamins are major constituents of the nuclear lamina, a filamentous meshwork underlying the inner nuclear envelope. In the other seven patients, a unique heterozygous insertion leading to the creation of a premature termination codon was identified in the gene ZMPSTE24, also known as FACE-1 in human. This gene encodes a metalloproteinase specifically involved in the post-translational processing of Lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of Lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of Lamin-associated proteins was evidenced. Our results indicate that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in all RD cases. RD is thus one of the most deleterious laminopathies identified so far in humans caused by (primary or secondary) A-type Lamin defects and nuclear structural and functional alterations.

* To whom correspondence should be addressed at: Inserm U491: ‘Génétique Médicale et Développement’, Faculté de Médecine de Marseille, 13385 Marseille Cedex 05, France. Tel: +33 491786894; Fax: +33 491804319; Email: nicolas.levy{at}medecine.univ-mrs.fr


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