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

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 articles^{2 - 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

Studies of LMNA and ZMPSTE24 may still be possible in the patient reported by Armbrust and colleagues.¹ Because their patient died after 24 days of life, which is somewhat unusual for patients with RD, the possibility exists that residual activity of the ZMPSTE24 gene is maintained together with mature lamin A or that a heterozygous mutation lies in the specific LMNA region encoding the lamin A isoform.

Their patient had symptoms that were unusual for RD. It may be possible that the heart defect in this child was related to the heart defect in her sibling and is in fact unrelated to the RD. Evaluation of the child’s sibling, perhaps using fluorescence in situ hybridization to search for a microdeletion of chromosome 22q11-13, seems warranted. Like the authors, we think these additional symptoms are unrelated to the RD. Finally, Armbrust et al¹ mention that a uniparental disomy was identified in a sibling with Silver-Russell syndrome. We are not informed which chromosome was involved, but it may be useful to search for a similar molecular mechanism in the proband as well. The presence in a single family of various and different disorders pleads for extensive additional studies to explain this and to provide adequate genetic counseling for the parents.

Correspondence: Dr Levy, Genetique Medicale et Development, Faculté de Médécine de la INSERM U491, 13385 Marseille, CEDEX 05, France (Nicolas.Levy@medecine.univ-mrs.fr).

Financial Disclosure: None.