Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs
Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs
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DOI：
10.1038/ng1549
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发表时间：
2005-05-01
期刊：
影响因子：
30.8
通讯作者：
Scambler, PJ
中科院分区：
文献类型：
--
作者：
Jadeja, S;Smyth, I;Scambler, PJ
Fraser综合征是一种隐性多系统疾病，表现为隐眼、并指和肾缺陷（1，2），并与细胞外基质蛋白FRAS 1的功能丧失突变相关。Fras 1突变小鼠具有水泡表型，其特征在于子宫内上皮脆性产生浆液性水泡，随后产生出血性水泡。髓脑泡（my）菌株具有相似的表型。我们将我定位到Frem 2，一个与Fras 1和Frem 1相关的基因，并表明Frem 2基因陷阱突变与我等位。在我的纯合子中，成人肾脏中Frem 2的表达与囊肿形成相关，表明该基因是维持肾上皮分化状态所必需的。两个患有弗雷泽综合征的个体就FREM 2的相同错义突变而言是纯合的，证实了遗传异质性。这是在任何起泡突变体或患有弗雷泽综合征的个体中报道的唯一错义突变，表明钙结合在CALX β-钙粘蛋白基序中对于FREM 2的正常功能是重要的。
Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects(1,2) and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs ( my) strain has a similar phenotype. We mapped my to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser syndrome, suggesting that calcium binding in the CALX beta-cadherin motif is important for normal functioning of FREM2.