Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.
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.
Inserm U491, Génétique Médicale et Développement, Faculté de Médecine de Marseille, Hôpital d'enfants de la Timone, Marseille, France.
Claire L
CL
Navarro
Annachiara
A
De Sandre-Giovannoli
Rafaëlle
R
Bernard
Irène
I
Boccaccio
Amandine
A
Boyer
David
D
Geneviève
Smail
S
Hadj-Rabia
Caroline
C
Gaudy-Marqueste
Henk Sillevis
HS
Smitt
Pierre
P
Vabres
Laurence
L
Faivre
Alain
A
Verloes
Ton
T
Van Essen
Elisabeth
E
Flori
Raoul
R
Hennekam
Frits A
FA
Beemer
Nicole
N
Laurent
Martine
M
Le Merrer
Pierre
P
Cau
Nicolas
N
Lévy
D001842:Bone and Bones / Q000002:abnormalities / Q000000981:diagnostic imaging; D002467:Cell Nucleus / Q000737:chemistry / Q000648:ultrastructure*; D005091:Exons / Q000235:genetics; D005333:Fetus / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn; D034904:Lamin Type A / Q000032:analysis / Q000235:genetics*; D008074:Lipoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008666:Metalloendopeptidases; D045726:Metalloproteases / Q000235:genetics*; D009154:Mutation; D034881:Nuclear Lamina / Q000473:pathology; D012326:RNA Splicing / Q000235:genetics; D011859:Radiography; D012867:Skin / Q000473:pathology; D012868:Skin Abnormalities / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D013577:Syndrome
D034904:Lamin Type A; D008074:Lipoproteins; D008565:Membrane Proteins; D045726:Metalloproteases; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human