Mild Recessive Mutations in Six Fraser Syndrome-Related Genes Cause Isolated Congenital Anomalies of the Kidney and Urinary Tract
Mild Recessive Mutations in Six Fraser Syndrome-Related Genes Cause Isolated Congenital Anomalies of the Kidney and Urinary Tract
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DOI：
10.1681/asn.2013101103
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发表时间：
2014-09-01
影响因子：
13.6
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
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作者：
Kohl, Stefan;Hwang, Daw-Yang;Hildebrandt, Friedhelm
在美国，先天性肾脏和泌尿道异常（CAKUT）约占ESRD儿童的40%。迄今为止，23个基因的突变已被描述为导致人类常染色体显性遗传孤立CAKUT。然而，>90%的孤立CAKUT病例仍然没有分子诊断。在这里，我们假设在隐性遗传小鼠模型中突变的基因具有单侧肾发育不全的特定CAKUT表型，也可能在患有孤立性CAKUT的人类中突变。我们应用新一代测序技术对来自590个家庭的574名CAKUT患者的12个隐性小鼠候选基因进行了靶向外显子测序。在590个家庭中的15个中，我们发现了基因FRAS 1、FREM 2、GRIP 1、FREM 1、ITGA 8和GREM 1的隐性突变，所有这些基因都在输尿管芽和后肾间充质的相互作用中起作用。我们发现，孤立CAKUT可能是由隐性基因突变部分。我们的研究结果还表明，在弗雷泽/MOTA/BNAR谱基因的双等位基因错义突变导致孤立的CAKUT，而截断突变被发现在多器官形式的弗雷泽综合征。新发现的隐性双等位基因突变在这六个基因代表孤立CAKUT的分子原因在2.5%的590个受影响的家庭在这项研究中。
Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.