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

Abstract

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.

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

“…The aim of our study was to explore in detail the transcriptional prelamin A-/lamin C-expression patterns associated to the different mutations, in either lymphoblastoid or fibroblast cell lines of the patients. We report for the first time the frequent expression of a 270-nt-deleted prelamin A transcript ('dermopathin') that had only been evidenced before in patients affected with restrictive dermopathy, 15 and correlate our findings to the presence of a common LMNA polymorphism previously described to affect lamin A-/C-expression levels and to the severity of the patients' clinical phenotypes.…”

“…[8][9][10] Other LMNA-dominant mutations have been associated with the production of progerin or other deleted prelamin A isoforms (prelamin AΔ35 and prelamin AΔ90). [11][12][13][14][15][16] We enrolled eight patients, including two sibs and a parent of a family in which the disease segregated on an autosomal dominant basis, carrying four different LMNA mutations affecting prelamin A splicing. The aim of our study was to explore in detail the transcriptional prelamin A-/lamin C-expression patterns associated to the different mutations, in either lymphoblastoid or fibroblast cell lines of the patients.…”

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

“…This pathology is caused either by dominant de novo LMNA mutations or more frequently by recessive null (homozygous or compound heterozygous) ZMPSTE24 mutations. Depending on the implicated mutation, a farnesylated truncated or wild‐type full prelamin A accumulates in nuclei (Navarro et al., 2004). The Zmpste24 ‐deficient mouse model (Zmpste24 −/− ) presents severe growth retardation and premature death associated with cardiomyopathy, muscular dystrophy, and lipodystrophy (Pendás et al., 2002).…”

Collagen expression in fibroblasts with a novel LMNA mutation

“…The most severe laminopathy, restrictive dermopathy, results in neonatal death. This disease is due to a splicing mutation that skips 90 amino acids of exon 11 [19]. Interestingly, ZMPSTE24 mutations are also reported in MAD and restrictive dermopathy [15,19].…”

“…This disease is due to a splicing mutation that skips 90 amino acids of exon 11 [19]. Interestingly, ZMPSTE24 mutations are also reported in MAD and restrictive dermopathy [15,19]. The most striking cardiovascular manifestations of HGPS is a form of severe atherosclerosis.…”