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Hum Mol Genet

Title:		"Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia"
Author(s):		Agarwal AK; Fryns JP; Auchus RJ; Garg A;
Address:		"Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA"
Journal Title:		Hum Mol Genet
Year:		2003
Volume:		12
Issue:		16
Page Number:		1995 - 2001
DOI:		10.1093/hmg/ddg213
ISSN/ISBN:		0964-6906 (Print) 0964-6906 (Linking)
Abstract:		"Mandibuloacral dysplasia (MAD; OMIM 248370) is a rare, genetically and phenotypically heterogeneous, autosomal recessive disorder characterized by skeletal abnormalities including hypoplasia of the mandible and clavicles, acro-osteolysis, cutaneous atrophy and lipodystrophy. A homozygous missense mutation, Arg527His, in the LMNA gene which encodes nuclear lamina proteins lamins A and C has been reported in patients with MAD and partial lipodystrophy. We studied four patients with MAD who had no mutations in the LMNA gene. We now show compound heterozygous mutations, Phe361fsX379 and Trp340Arg, in the zinc metalloproteinase (ZMPSTE24) gene in one of the four patients who had severe MAD associated with progeroid appearance and generalized lipodystrophy. ZMPSTE24 is involved in post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A in two steps to form mature lamin A. Deficiency of Zmpste24 in mice causes accumulation of prelamin A and phenotypic features similar to MAD. The yeast homolog, Ste24, has a parallel role in processing of prenylated mating pheromone a-factor. Since human ZMPSTE24 can also process a-factor when expressed in yeast, we assessed the functional significance of the two ZMPSTE24 mutations in the yeast to complement the mating defect of the haploid MATa yeast lacking STE24 and Ras-converting enzyme 1 (RCE1; another prenylprotein-specific endoprotease) genes. The ZMPSTE24 mutant construct, Phe361fsX379, was inactive in complementing the yeast a-factor but the mutant, Trp340Arg, was partially active compared to the wild type ZMPSTE24 construct. We conclude that mutations in ZMPSTE24 may cause MAD by affecting prelamin A processing"
Keywords:		"Abnormalities, Multiple/etiology/*genetics Acro-Osteolysis/genetics Atrophy/genetics Clavicle/abnormalities Humans Lamin Type A/genetics Lipodystrophy/genetics Lipoproteins/*genetics/metabolism Mandible/*abnormalities Membrane Proteins/*genetics/metabolis;"
Notes:		"MedlineAgarwal, Anil K Fryns, Jean-Pierre Auchus, Richard J Garg, Abhimanyu eng M01-RR00633/RR/NCRR NIH HHS/ R01-DK54387/DK/NIDDK NIH HHS/ Comparative Study Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. England 2003/08/13 Hum Mol Genet. 2003 Aug 15; 12(16):1995-2001. doi: 10.1093/hmg/ddg213"