Original Article
Homozygous and Compound Heterozygous Mutations in ZMPSTE24 Cause the Laminopathy Restrictive Dermopathy

https://doi.org/10.1111/j.0022-202X.2005.23846.xGet rights and content
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Restrictive dermopathy (RD) is a lethal human genetic disorder characterized by very tight, thin, easily eroded skin, rocker bottom feet, and joint contractures. This disease was recently reported to be associated with a single heterozygous mutation in ZMPSTE24 and hypothesized to be a digenic disorder (Navarro et al, Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet 13:2493–2503, 2004). ZMPSTE24 encodes an enzyme necessary for the correct processing and maturation of lamin A, an intermediate filament component of the nuclear envelope. Here we present four unrelated patients with homozygous mutations in ZMPSTE24 and a fifth patient with compound heterozygous mutations in ZMPSTE24. Two of the three different mutations we found are novel, and all are single base insertions that result in messenger RNA frameshifts. As a consequence of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was detected in the nuclei of both cultured cells and tissue from RD patients, but not in control nuclei. Abnormally aggregated lamin A/C was also observed. These results indicate that RD is an autosomal recessive laminopathy caused by inactivating ZMPSTE24 mutations that result in defective processing and nuclear accumulation of prelamin A.

Keywords

FATP4 protein
lamin A
nuclear envelope
STE24 protein

Cited by (0)

After this paper was accepted, we found a novel ZMPSTE24 nonsense mutation, c.691G>T, predicted to encode p.Glu231X, in both parents of an affected child from southern India. DNA from the child was not available, but we consider this to be a pathogenic mutation.

Navarro et al. recently published a paper (Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors. Hum Mol. Genet 14:1503–1513, 2005) showing that both alleles of ZMPSTE24 are in fact mutated in their patients with restrictive dermopathy; these patients were previously reported to carry only heterozygous mutations. Based on these new findings, they have withdrawn their hypothesis of digenic inheritance.