Mutations in TMEM231 cause Joubert syndrome in French Canadians
Mutations in TMEM231 cause Joubert syndrome in French Canadians
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DOI：
10.1136/jmedgenet-2012-101132
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发表时间：
2012-10-01
影响因子：
4
通讯作者：
Michaud, Jacques L.
中科院分区：
文献类型：
--
作者：
Srour, Myriam;Hamdan, Fadi F.;Michaud, Jacques L.
Joubert综合征（JBTS）是一种常染色体隐性遗传病，主要表现为中脑畸形、动眼肌失用症、呼吸异常和发育迟缓。JBTS具有遗传异质性，涉及非运动性纤毛形成和功能所需的基因。本文研究了12名法裔加拿大人（FC）的JBTS遗传基础。方法和结果所有受试者的外显子组测序结果显示，其中6例患者携带罕见的已知JBTS基因CC2D2A或C5ORF42复合杂合突变。此外，三个个体（两个家族）为TMEM231中相同的罕见突变的复合杂合(c。12 t > (p.Tyr4 *);c.625G > [p.Asp209Asn])。所有三名受试者都表现出严重的神经表型和多指畸形、视网膜病变和肾囊肿的可变存在。在385例FC对照中未检测到这些突变。TMEM231先前已被证明定位于纤毛过渡区，并在一个涉及纤毛和质膜之间扩散屏障形成的复合物中与几个JBTS基因产物相互作用。TMEM231的siRNA敲低也被证明会影响屏障的完整性，导致纤毛形成减少和信号受体的纤毛定位。我们的数据表明，TMEM231突变导致JBTS，加强了这种情况与纤毛过渡区屏障破坏之间的关系。
Background Joubert syndrome (JBTS) is a predominantly autosomal recessive disorder characterised by a distinctive midhindbrain malformation, oculomotor apraxia, breathing abnormalities and developmental delay. JBTS is genetically heterogeneous, involving genes required for formation and function of non-motile cilia. Here we investigate the genetic basis of JBTS in 12 French-Canadian (FC) individuals.Methods and results Exome sequencing in all subjects showed that six of them carried rare compound heterozygous mutations in CC2D2A or C5ORF42, known JBTS genes. In addition, three individuals (two families) were compound heterozygous for the same rare mutations in TMEM231(c. 12T>A[p.Tyr4*]; c.625G> A[p.Asp209Asn]). All three subjects showed a severe neurological phenotype and variable presence of polydactyly, retinopathy and renal cysts. These mutations were not detected among 385 FC controls. TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. siRNA knockdown of TMEM231 was also shown to affect barrier integrity, resulting in a reduction of cilia formation and ciliary localisation of signalling receptors.Conclusions Our data suggest that mutations in TMEM231 cause JBTS, reinforcing the relationship between this condition and the disruption of the barrier at the ciliary transition zone.