Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.

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Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.

Restrictive dermopathy (RD) is a rare, severe, lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence. To date, about 60 cases of RD were described. The signs of the disease are very characteristic and include intrauterine growth retardation, thin, tightly adherent translucent skin, superficial vessels, typical facial dysmorphism as well as generalized joint contractures. The syndrome is caused in most cases by ZMPSTE24 autosomal recessive mutations, or, less frequently, by LMNA autosomal dominant mutations. We report on two brothers affected with RD, who died in the neonatal period. Molecular analyses were performed in the second child, for whom biological material was available, and both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by the parents' genomic analysis. Besides, a review of the mutations causing RD is made.

Background and Purpose-Laminopathies arise through mutations in genes encoding Lamin A/C (LMNA) or associated proteins. They cause 4 different groups of disorders with diverse severity and often overlapping features: diseases of striated muscle (leading to muscular or cardiac involvement), peripheral neuropathy, lipodystrophy syndromes, and accelerated aging disorders. Summary of Case-We report on a familial case of atypical Werner syndrome (a progeroid syndrome with Werner syndrome phenotype but without typical RECQL2 mutation) presenting with acute ischemic cerebral disease or peripheral artery disease associated with diffuse atherosclerosis, attributable to transmission of a novel LMNA mutation. Conclusions-In young patients with ischemic events and a positive family history, other progeroid features have to be searched and LMNA testing has to be considered, allowing for genetic counseling and presymptomatic testing of at-risk relatives. (Stroke. 2009;40:e11-e14.)

BACKGROUND Lamins are proteins of the nuclear envelope involved in 'laminopathies', an heterogeneous group of diseases sharing clinical similarities with systemic sclerosis (SSc). Methods In this context, a search was undertaken for mutations in LMNA, encoding Lamins A/C, and ZMPSTE24, LBR, LMNB1, LMNB2, MAN1, SYNE1a and LAP2, encoding Lamins A/C molecular partners, in a Caucasian woman affected with Reynolds syndrome, a particular nosologic entity specifically associating limited cutaneous SSc and primary biliary cirrhosis. RESULTS Coding regions and intron-exon boundaries of these genes were PCR amplified and sequenced, revealing a single heterozygous missense mutation in LBR exon 9 (c.1114C/T; p.R372C). This variant was absent in 400 control chromosomes. The mutation was predicted to induce a change in Lamin B receptor (LBR) tertiary structure and molecular interactions by bioinformatic tools. Further functional explorations were performed on the patient's fibroblasts and lymphoblastoid cell lines. On the latter, the expression levels of LBR, Lamins A/C, Lamin B1, Lamin B2, and HP1a were conserved. Conversely, in the patient's skin fibroblasts, LBR and the aforementioned molecular partners showed dramatically reduced or abolished expression levels. The immunofluorescence analyses performed on both cell lines corroborated these findings. CONCLUSION The fibroblast specific abnormalities observed suggest that this particular LBR mutation might have dominant negative deleterious effects in a tissue specific fashion, possibly through the perturbation of the interactions or stability of the nuclear envelope protein network. LBR mutations might thus be associated with Reynolds syndrome.

A 4-day-old boy presented with tight, translucent skin, prominent vessels, skin erosions, and dysmorphic findings, including hypertelorism, antimongoloid axis, sparse eyelashes and eyebrows, pinched nose, natal teeth, microretrognathia, and an "o-shaped" mouth. Multiple joint contractures, dysplastic clavicles, and thin ribs were also observed. He died at 2 weeks of age of respiratory distress. The patient was diagnosed as being affected with restrictive dermopathy, which is a rare, lethal genodermatosis caused by recessive mutations of the zinc metalloproteinase ZMPSTE24 gene or less frequently, by dominant lamin A/C gene mutations. Direct sequencing of the ZMPSTE24 gene was performed, and the most common, homozygous, inactivating mutation in exon 9 was identified in the patient (c.1085_1086insT; p.Leu362PhefsX19). Autosomal recessive transmission was confirmed by parental DNA analysis. After genetic counseling, a prenatal diagnosis could be performed during the subsequent pregnancy. ZMPSTE24 screening was performed by direct sequencing and fluorescent fragment analysis on DNA derived from a chorionic villus sample after exclusion of maternal contamination. The fetus had inherited both normal parental alleles, avoiding the recurrence of the disease.