[Skip to Navigation]
November 2005

Defective Prelamin A Processing Resulting From LMNA or ZMPSTE24 Mutations as the Cause of Restrictive Dermopathy

Arch Dermatol. 2005;141(11):1473-1474. doi:10.1001/archderm.141.11.1473-b

Armbrust and colleagues1 report a case of a child with restrictive dermopathy (RD) who had unusual symptoms: a transposition of the great arteries and a microcolon. The authors state that RD is an autosomal recessive disorder of unknown cause and suggest that the FATP4 gene is pathogenetically involved.

We were surprised by their article. The authors must have missed our recent articles2,3 in which we demonstrated that RD is caused either by mutations in the LMNA gene, encoding A-type lamins, or in the ZMPSTE24 gene, encoding a metalloprotease essential for the posttranslational processing of prelamin A to mature lamin A.2,3 As such, RD can be either autosomal dominant, as in the case of de novo splicing mutations in LMNA, or autosomal recessive, as in the case of loss of function mutations in ZMPSTE24.2,3 In the latter case, patients with these mutations have been found to be either homozygous or compound heterozygous.3 We have examined a total of 12 patients with RD and have identified mutations in all of them. Furthermore, major nuclear disorganization was observed, with accumulation of either truncated or normal-length prelamin A.2,3 Accumulation of lamin A precursors has a dramatically toxic effect on RD cells, as confirmed in recent studies4 performed on knockout mouse models for LMNA and ZMPSTE24. Our findings rule out mutations in the FATP4 gene as a potential cause for most cases of RD, despite the features resembling RD described in targeted disruption of FATP4 in mice.1 To date, the closest model for RD corresponds to the ZMPSTE24 knockout mouse.5 Thus, RD can be added to the group of laminopathies that consists of more than 10 different disorders. It most resembles the premature aging disorder progeria, which was previously associated with lamin A truncation.6