Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.
Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.
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DOI：
10.1371/journal.pone.0051622
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rozet JM
中科院分区：
文献类型：
--
作者：
Perrault I;Estrada-Cuzcano A;Lopez I;Kohl S;Li S;Testa F;Zekveld-Vroon R;Wang X;Pomares E;Andorf J;Aboussair N;Banfi S;Delphin N;den Hollander AI;Edelson C;Florijn R;Jean-Pierre M;Leowski C;Megarbane A;Villanueva C;Flores B;Munnich A;Ren H;Zobor D;Bergen A;Chen R;Cremers FP;Gonzalez-Duarte R;Koenekoop RK;Simonelli F;Stone E;Wissinger B;Zhang Q;Kaplan J;Rozet JM
Leber先天性黑蒙（LCA）是最早和最严重的视网膜变性（RD），也是最常见的儿童无法治愈的失明原因。它偶尔是多系统纤毛病的表现症状，诊断需要对患者进行特殊护理。目前已鉴定出19个LCA基因，其中3个基因可解释该疾病的非综合征型和综合征型。RD 3（LCA 12）被认为是LCA基因的基础上鉴定的纯合截断突变的两个LCA家庭，尽管筛选的大队列的患者。在这里，我们提供了一个全面的调查RD 3突变和他们的临床表现，通过筛选一个队列的852例患者来自世界各地的LCA或早发性和严重的RD。我们在7个不相关的近亲LCA家族中发现了3个RD 3突变，一个2bp的缺失和两个无义突变-预测会导致功能完全丧失。来自地中海南岸的五个家庭分离出类似的突变（c.112C>T，p.R38*），表明这种变化可能是由古代创始人效应造成的。考虑到RD 3携带者的低频率，杂合子和纯合子RD 3个体在非血缘结合中LCA的复发风险可以忽略不计。我们患者的LCA 12表型与突变型光受体特异性鸟苷酸环化酶（GUCY 2D/LCA 1）患者的表型高度相似。这一观察结果与RD 3在GUCYs运输中的作用的报道一致，并进一步支持LCA 12和LCA 1中感光细胞变性的共同机制，即，不能增加外节中的细胞质cGMP浓度，从而不能恢复暗状态。与LCA 1相似，LCA 12患者尽管两个RD 3等位基因完全失活，但没有眼外症状，支持应避免对RD 3突变的LCA婴儿进行眼外检查的观点。
Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations – predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3 mutations should be avoided.
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影响因子：
30.8
作者：
Falk, Marni J.;Zhang, Qi;Nakamaru-Ogiso, Eiko;Kannabiran, Chitra;Fonseca-Kelly, Zoe;Chakarova, Christina;Audo, Isabelle;Mackay, Donna S.;Zeitz, Christina;Borman, Arundhati Dev;Staniszewska, Magdalena;Shukla, Rachna;Palavalli, Lakshmi;Mohand-Said, Saddek;Waseem, Naushin H.;Jalali, Subhadra;Perin, Juan C.;Place, Emily;Ostrovsky, Julian;Xiao, Rui;Bhattacharya, Shomi S.;Consugar, Mark;Webster, Andrew R.;Sahel, Jose-Alain;Moore, Anthony T.;Berson, Eliot L.;Liu, Qin;Gai, Xiaowu;Pierce, Eric A.
通讯作者：
Pierce, Eric A.
影响因子：
64.8
作者：
Dib, C;Faure, S;Weissenbach, J
通讯作者：
Weissenbach, J
影响因子：
30.8
作者：
Gal, A;Li, Y;Vollrath, D
通讯作者：
Vollrath, D
影响因子：
30.8
作者：
Janecke, AR;Thompson, DA;Gal, A
通讯作者：
Gal, A
影响因子：
9.8
作者：
Friedman, James S.;Chang, Bo;Swaroop, Anand
通讯作者：
Swaroop, Anand