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

Hutchinson–Gilford progeria syndrome (HGPS) is a rare but devastating genetic disorder that mimics premature aging. Most cases are caused by heterozygous mutations in LMNA, encoding lamin A/C. The allelic disorder, mandibuloacral dysplasia (MAD), shares many features with HGPS and can also result from homozygous mutations in ZMPSTE24, which encodes the enzyme responsible for proteolytic processing of prelamin A. Heterozygous mutation of ZMPSTE24 was recently found to be associated with restrictive dermopathy (RD), a lethal neonatal disorder characterised by tight skin and sharing features of MAD/HGPS. N Compound heterozygous ZMPSTE24 mutations, c.1085_1086insT (Leu362PhefsX19) and c.794 ARG (N265S), were identified in a two year old girl with a severe early onset progeroid phenotype displaying features of HGPS, MAD, and RD. N Western blot analysis of skin fibroblasts showed defective lamin A processing, resulting in reduced levels of mature lamin A and increased levels of the prelamin A precursor. N Primary skin fibroblasts showed abnormal nuclear morphology and these abnormalities increased in severity upon culturing. N Our data widen the spectrum of progeroid phenotypes associated with ZMPSTE24 mutation and for the first time provide evidence that these mutations lead to defective prelamin A processing and abnormal nuclear morphology in humans.