Compound heterozygous alterations in intraflagellar transport protein CLUAP1 in a child with a novel Joubert and oral-facial-digital overlap syndrome
Compound heterozygous alterations in intraflagellar transport protein CLUAP1 in a child with a novel Joubert and oral-facial-digital overlap syndrome
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DOI：
10.1101/mcs.a001321
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发表时间：
2017-07-01
影响因子：
1.8
通讯作者：
Biesecker, Leslie G.
中科院分区：
文献类型：
--
作者：
Johnston, Jennifer J.;Lee, Chanjae;Biesecker, Leslie G.
正常纤毛功能的破坏导致一系列疾病统称为纤毛病。在这里，我们报告一个儿童的表型与Joubert，口腔-面部-数字和Pallister-Hall综合征重叠，包括脑，肢体和颅面异常。我们对先证者和父母双方进行了外显子组序列分析，过滤了假定的致病变异和sanger验证的感兴趣的变异。在爪蟾系统中对鉴定出的CLUAP1变异进行功能分析，以确定其对纤毛功能的影响。通过外显子组序列分析鉴定出CLUAP1的两个变异Chr16:g。3558407T>G, c.338T>G, p.（Met113Arg）和Chr16: G . 3570011c >T, c.688C>T, p.（Arg230Ter）。这些变异在ExAC (Exome Aggregation Consortium) 65,000个个体的数据集中是罕见的（分别出现一次和两次）。将CLUAP1突变体转染到爪蟾胚胎中，发现蛋白水平p.（Arg230Ter）和鞭毛内转运p.（Met113Arg）降低。遗传数据表明，这些变异存在于受影响的儿童中，在人群中很少见，并导致鞭毛内运输减少，但并非没有。我们得出结论，clap1的双等位基因突变导致了先证者的这种新型纤毛病综合征。
Disruption of normal ciliary function results in a range of diseases collectively referred to as ciliopathies. Here we report a child with a phenotype that overlapped with Joubert, oral-facial-digital, and Pallister-Hall syndromes including brain, limb, and craniofacial anomalies. We performed exome-sequence analysis on a proband and both parents, filtered for putative causative variants, and Sanger-verified variants of interest. Identified variants in CLUAP1 were functionally analyzed in a Xenopus system to determine their effect on ciliary function. Two variants in CLUAP1 were identified through exome-sequence analysis, Chr16:g.3558407T>G, c.338T>G, p.(Met113Arg) and Chr16: g.3570011C>T, c.688C>T, p.(Arg230Ter). These variants were rare in the Exome Aggregation Consortium (ExAC) data set of 65,000 individuals (one and two occurrences, respectively). Transfection of mutant CLUAP1 constructs into Xenopus embryos showed reduced protein levels p.(Arg230Ter) and reduced intraflagellar transport p.(Met113Arg). The genetic data show that these variants are present in an affected child, are rare in the population, and result in reduced, but not absent, intraflagellar transport. We conclude that biallelic mutations in CLUAP1 resulted in this novel ciliopathy syndrome in the proband.