Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis
Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis
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DOI：
10.1086/378781
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发表时间：
2003-10-01
影响因子：
9.8
通讯作者：
Martignetti, JA
中科院分区：
文献类型：
--
作者：
Dowling, O;Difeo, A;Martignetti, JA
幼年型透明纤维瘤病（JHF）和婴儿型系统性玻璃样变性（ISH）是病因不明的常染色体隐性遗传综合征，其特征为多发性、复发性皮下肿瘤、牙龈肥大、关节挛缩、骨质溶解和骨质疏松。两者都被认为是等位基因疾病; ISH与JHF的区别在于其更严重的表型，包括多个器官中的透明质沉积物，复发性感染和生命最初2年内的死亡。使用先前报道的染色体4 q21 JHF疾病位点作为候选基因鉴定的指导，我们确定并表征了毛细血管形态发生因子-2基因（CMG 2）中的JHF和ISH致病突变。虽然CMG 2编码的蛋白质在毛细血管形成过程中的内皮细胞上调，最近被证明作为炭疽毒素受体的功能，其生理作用尚不清楚。两个ISH家族特异性截短突变，E220 X和1-bp插入P357 insC，导致翻译框外终止密码子，通过定点诱变产生，并显示删除CMG 2跨膜和/或胞质结构域，分别。一个ISH复合突变，I189 T，预计在蛋白质内产生一个新的和不稳定的内部空腔。JHF家族特异性同源等位基因错义突变G105 D使vonWillebrand因子A胞外结构域α-螺旋不稳定，而另一个突变L329 R发生在蛋白质的跨膜结构域内。最后，并可能提供深入了解这些疾病的病理生理学，来自JHF或ISH患者的成纤维细胞的分析表明，CMG 2突变废除正常细胞与细胞外基质的相互作用。
Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive syndromes of unknown etiology characterized by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis. Both are believed to be allelic disorders; ISH is distinguished from JHF by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections, and death within the first 2 years of life. Using the previously reported chromosome 4q21 JHF disease locus as a guide for candidate-gene identification, we identified and characterized JHF and ISH disease-causing mutations in the capillary morphogenesis factor-2 gene (CMG2). Although CMG2 encodes a protein upregulated in endothelial cells during capillary formation and was recently shown to function as an anthrax-toxin receptor, its physiologic role is unclear. Two ISH family-specific truncating mutations, E220X and the 1-bp insertion P357insC that results in translation of an out-of-frame stop codon, were generated by site-directed mutagenesis and were shown to delete the CMG2 transmembrane and/or cytosolic domains, respectively. An ISH compound mutation, I189T, is predicted to create a novel and destabilizing internal cavity within the protein. The JHF family-specific homoallelic missense mutation G105D destabilizes a vonWillebrand factor A extracellular domain alpha-helix, whereas the other mutation, L329R, occurs within the transmembrane domain of the protein. Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.