Human Molecular Genetics Advance Access published online on August 18, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh265
© 2004 by Oxford University Press
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1 Inserm U491 : "Génétique Médicale et Développement", Faculté de Médecine de Marseille, France
* To whom correspondence should be addressed. E-mail: nicolas.levy{at}medecine.univ-mrs.fr.
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 was evidenced, as well as abnormal patterns of nuclear sizes and shapes, and mislocalization of Lamin-associated proteins. Our results indicate that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in all RD cases. Restrictive Dermopathy is thus one of the most deleterious laminopathies identified so far in humans, due to (primary or secondary) A-type Lamin defects and to nuclear structural and functional alterations.
Article
Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganisation and identify restrictive dermopathy as a lethal neonatal laminopathy
2 Département de Génétique Médicale, Hôpital d'enfants de la Timone, Marseille, France
3 Inserm U491 : "Génétique Médicale et Développement", Faculté de Médecine de Marseille, France; Département de Génétique Médicale, Hôpital d'enfants de la Timone, Marseille, France
4 Inserm U393, Hôpital Necker enfants malades, Paris, France
5 Service de dermatologie pédiatrique, Hôpital Necker enfants malades, Paris, France
6 Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands
7 Service de Dermatologie, CHU Poitiers, France
8 Centre de Génétique, CHU de Dijon, France
9 Service de Génétique, Hôpital Robert Debré, Paris, France
10 Department of Clinical Genetics, University Hospital, Groningen, The Netherlands
11 Service de Cytogénétique, Hôpital de Hautepierre, Strasbourg, France
12 Department of Pediatrics and Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
13 Clinical Genetics Center, University Medical Center, Utrecht, The Netherlands
14 Service d'Anatomie-Pathologique, CHU de Dijon, France
15 Inserm U491 : "Génétique Médicale et Développement", Faculté de Médecine de Marseille, France; Laboratoire de Biologie Cellulaire, Hôpital Conception, Marseille, France. (1, 2 and 14 are part of the Institut Fédératif de Physiopathologie Humaine de Marseille - IFR 125)
16 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
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