Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype.

H utchinson–Gilford progeria syndrome (HGPS; OMIM 176670) is an extremely rare but devastating disorder that mimics premature aging. Affected children appear normal at birth but typically develop failure to thrive in the first two years. Other features include alopecia, micrognathia, loss of subcutaneous fat with prominent veins, abnormal dentition, sclerodermatous skin changes, and osteolysis of the clavicles and distal phalanges. The mean age of death is at age 13 years, most commonly due to atherosclerosis. HGPS is mainly sporadic in occurrence, but a genetic cause has now been implicated following the identification of de novo heterozygous mutations in the LMNA gene in the majority of HGPS patients. 5 A single family showing autosomal recessive inheritance of homozygous LMNA mutations has also been reported. LMNA encodes lamins A and C, components of the nuclear lamina, a meshwork underlying the nuclear envelope that serves as a structural support and is also thought to contribute to chromatin organisation and the regulation of gene expression. 8 Interestingly, mutations in LMNA have recently been associated with at least eight inherited disorders, known as laminopathies, with differential dystrophic effects on a variety of tissues including muscle, neurones, skin, bone, and adipose tissue (reviewed in Mounkes et al). However, the realisation that these disorders share common genetic defects has led to clinical reevaluation, with emerging evidence of significant phenotypic overlap. Hence the laminopathies might reasonably be considered as a spectrum of related diseases. HGPS has phenotypic similarities to several other laminopathies, in particular the atypical Werner’s syndrome and mandibuloacral dysplasia (MAD; OMIM 248370 and 608612). These diseases are associated with lipodystrophy, 13 which is the most prominent feature of another laminopathy, familial partial lipodystrophy of the Dunnigan variety (OMIM 151660). MAD has been further classified as two types according to whether the fat loss affects only the extremities (MADA) or is generalised (MADB). Patients with classical HGPS, caused by heterozygous mutation of the LMNA gene, appear to show some skeletal anomalies typical of MAD, including micrognathia and osteolysis of the distal phalanges and clavicles. However, a kindred with an atypical form of HGPS, with homozygous LMNA mutations revealed the more prominent radiological features of MAD, including acro-osteolysis and hypoplasia or absence of the clavicles. 15 In addition to LMNA, MADB has been associated with compound heterozygous mutation of the ZMPSTE24 gene, which encodes a zinc metalloproteinase necessary for the proteolytic processing of prelamin A to form mature lamin A. This involves farnesylation of the cysteine residue within the C-terminal CAAX motif of prelamin A, followed by removal of the AAX by ZMPSTE24. The cysteine residue is then methylated and a final proteolytic cleavage, now also thought to be performed by ZMPSTE24, removes a further 15 C-terminal residues to produce mature lamin A. In agreement with this, Zmpste24 knock-out mice are unable to process prelamin A and have a phenotype reminiscent of human laminopathies. 19 Recently, mutations in LMNA and Key points