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

Claire L. Navarro (1) , Annachiara de Sandre-Giovannoli (1, 2) , Rafaelle Bernard (1, 2) , Irène Boccaccio (1) , Amandine Boyer (2) , David Geneviève (3) , Smail Hadj-Rabia (4, 5) , Caroline Gaudy-Marqueste (2) , Henk Sillevis Smitt (6) , Pierre Vabres (7, 8) , Laurence Faivre (7, 9) , Alain Verloes (10) , Ton van Essen (11) , Elisabeth Flori (12) , Raoul Hennekam (6) , Frits A Beemer (13) , Nicole Laurent (14) , Martine Le Merrer (3) , Pierre Cau (1, 15) , Nicolas Levy (1, 2)

1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 Département de génétique médicale [Hôpital de la Timone - APHM]
3 Inserm U393 - Handicaps génétiques de l'enfant
4 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
5 Service de dermatologie pédiatrique
6 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
7 GAD - Génétique des Anomalies du Développement
8 CHU de Poitiers - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
9 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
10 Unité fonctionnelle de génétique clinique
11 Department of Human Genetics
12 Service de cytogénétique
13 University Medical Center [Utrecht]
14 Service de Pathologie [CHU de Dijon]
15 Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM]

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.

Domaines: Biologie moléculaire; Génétique humaine; Dermatologie

Claire L. Navarro, Annachiara de Sandre-Giovannoli, Rafaelle Bernard, Irène Boccaccio, Amandine Boyer, et al.. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Human Molecular Genetics, 2004, 13 (20), pp.2493 - 2503. ⟨10.1093/hmg/ddh265⟩. ⟨hal-01668977⟩