ZMPSTE24的纯合子和复合杂合子突变引起核纤层病变性限制性皮病  

Homozygous and compound heterozygous mutations in ZMPSTE24 cause the lamino-pathy restrictive dermopathy

作　　者：Moulson C.L. Go G. Gardner J.M. J.H. Miner 朱国兴 

机构地区：[1]Renal Division,Box 8126,Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, United States Dr.

出　　处：《世界核心医学期刊文摘（皮肤病学分册）》2006年第8期18-19,共2页Digest of the World Core Medical JOurnals:Dermatology

摘　　要：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.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,

关 键 词：复合杂合子 突变位点 纯合子 皮病 核纤层 变性 信使RNA 4基因 特征表现 

分 类 号：R556.502[医药卫生—血液循环系统疾病] R978.19[医药卫生—内科学]