Mutation of POC1B in a severe syndromic retinal ciliopathy.
Mutation of POC1B in a severe syndromic retinal ciliopathy.
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严重综合征性视网膜纤毛病中的 POC1B 突变。
DOI：
10.1002/humu.22618
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发表时间：
2014-10
期刊：
影响因子：
3.9
通讯作者：
Bolz, Hanno J.
中科院分区：
文献类型：
--
作者：
Beck, Bodo B.;Phillips, Jennifer B.;Bartram, Melte P.;Wegner, Jeremy;Thoenes, Michaele;Pannes, Andrea;Sampson, Josephina;Heller, Raoul;Goebel, Heike;Koerber, Friederike;Neugebauer, Antje;Hedergott, Andrea;Nuernberg, Gudrun;Nuernberg, Peter;Thiele, Holger;Altmueller, Janine;Toliat, Mohammad R.;Staubach, Simon;Boycott, Kym M.;Valente, Enza Maria;Janecke, Andreas R.;Eisenberger, Tobias;Bergmann, Carsten;Tebbe, Lars;Wang, Yang;Wu, Yundong;Fry, Andrew M.;Westerfield, Monte;Wolfrum, Uwe;Bolz, Hanno J.
我们描述了一个伊拉克近亲家族，患有莱伯先天性黑蒙（LCA）、朱伯特综合征（JBTS）和多囊肾病。针对排除已知LCA和JBTS基因突变的NGS，纯合性作图和全外显子组测序鉴定了POC 1B中的纯合错义变体c.317G>C（p.Arg106Pro），POC 1B是纤毛发生、基体和中心体完整性所必需的基因。计算机模拟表明需要p.Arg106形成第三个WD 40重复序列和蛋白质相互作用界面。在人和小鼠视网膜中，POC 1B定位于基底体和中心粒，邻近光感受器的连接纤毛和外丛状层的突触。在斑马鱼中敲除Poc 1b导致囊性肾和视网膜变性，伴随着光感受器连接纤毛的缩短和减少，与人类综合征性纤毛病相一致。最近的一项研究描述了一个非综合征性视锥-视杆细胞营养不良家族中p.Arg106ProPOC1B的纯合性。因此，与纯合p.Arg106ProPOC1B相关的表型可能是高度可变的，类似于WDR 19中引起孤立性视网膜色素变性或Jeune综合征的纯合p.Leu710Ser。我们的研究表明，POC 1B是视网膜完整性所必需的，我们提出POC 1B突变是严重多囊肾病JBTS的可能原因。
We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease. Targeted NGS for excluding mutations in known LCA and JBTS genes, homozygosity mapping and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with non-syndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe polycystic kidney disease.
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影响因子：
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通讯作者：
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作者：
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通讯作者：
Arnaud, Lionel