1. ^*Department of Internal Medicine, Renal Division, St Louis, Missouri, USA
2. ^†Department of Genetics, Washington University School of Medicine, St Louis, Missouri, USA
3. ^‡Department of Cardiovascular Pathology, Academic Medical Center, Amsterdam, The Netherlands
4. ^§Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands
5. ^¶Department of Clinical Genetics and Human Genetics, VU University Medical Center, Amsterdam, The Netherlands
6. ^#Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, Missouri, USA

Correspondence: Dr Jeffrey H. Miner, Renal Division, Box 8126, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, Missouri 63110, USA. Email: minerj@wustl.edu

Received 4 February 2005; Revised 11 April 2005; Accepted 3 May 2005; Published online 25 October 2005.

Abstract

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.