Agarwal Anil K, Fryns Jean-Pierre, Auchus Richard J, Garg Abhimanyu
Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
Hum Mol Genet. 2003 Aug 15;12(16):1995-2001. doi: 10.1093/hmg/ddg213.
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.
下颌骨发育不全综合征（MAD；OMIM 248370）是一种罕见的、具有遗传和表型异质性的常染色体隐性疾病，其特征为骨骼异常，包括下颌骨和锁骨发育不全、肢端骨质溶解、皮肤萎缩和脂肪营养不良。据报道，患有MAD和部分脂肪营养不良的患者中，编码核纤层蛋白A和C的LMNA基因存在纯合错义突变Arg527His。我们研究了4名LMNA基因无突变的MAD患者。现在我们发现，在4名患有严重MAD且伴有早老样外观和全身脂肪营养不良的患者中，有1名患者的锌金属蛋白酶（ZMPSTE24）基因存在复合杂合突变Phe361fsX379和Trp340Arg。ZMPSTE24参与法尼基化前体核纤层蛋白A羧基末端残基的两步翻译后蛋白水解切割，以形成成熟的核纤层蛋白A。小鼠中Zmpste24缺乏会导致前体核纤层蛋白A积累，并出现与MAD相似的表型特征。酵母同源物Ste24在法尼基化交配信息素α因子的加工过程中具有类似作用。由于人类ZMPSTE24在酵母中表达时也能加工α因子，我们在酵母中评估了这两种ZMPSTE24突变的功能意义，以补充缺乏STE24和Ras转换酶1（RCE1；另一种异戊二烯化蛋白特异性内切蛋白酶）基因的单倍体MATa酵母的交配缺陷。ZMPSTE24突变体构建体Phe361fsX379在补充酵母α因子方面无活性，但与野生型ZMPSTE24构建体相比，突变体Trp340Arg具有部分活性。我们得出结论，ZMPSTE24突变可能通过影响前体核纤层蛋白A的加工而导致MAD。
