Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations.
Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations.
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DOI：
10.1371/journal.pone.0023021
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Daiger SP
中科院分区：
文献类型：
--
作者：
Fahim AT;Bowne SJ;Sullivan LS;Webb KD;Williams JT;Wheaton DK;Birch DG;Daiger SP
RPGR中的突变占X连锁视网膜色素变性（XRP）的70%以上，其特征在于视网膜变性和最终失明。RPGR突变的临床后果是高度不同的，即使在具有相同突变的个体之间：男性表现出广泛的临床严重性，女性携带者可能会或可能不会受到影响。这项研究描述了来自56个RPGR突变家族的98名受影响男性的表型多样性，并证明了遗传因素（即，等位基因异质性和遗传修饰剂）对这种多样性的影响。根据具体临床标准，将患者分为1级（轻度）、2级（中度）或3级（重度）。对患者DNA进行基因分型，以确定4种候选修饰基因中编码SNP的基因型，已知这些修饰基因具有与RPGR蛋白相互作用的产物：RPGRIP 1、RPGRIP 1 L、CEP 290和IQCB 1。使用PLINK进行基于家族的关联性检验。在家族间和家族内均观察到广泛的临床严重程度。外显子1-14突变的患者比ORF 15突变的患者受到的影响更严重，预测无效等位基因的患者比预测产生RPGR蛋白的患者受到的影响更严重。两个SNP显示与严重疾病相关：IQCB 1中I393 N的次要等位基因（N）（p = 0.044）和RPGRIP 1 L中R744 Q的常见等位基因（R）（p = 0.049）。 这些数据表明等位基因异质性有助于XlRP的表型多样性，并表明这可能取决于RPGR蛋白的存在或不存在。此外，已知与RPGR相互作用的2种蛋白质中的常见变体与该队列中的严重疾病相关。
Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers) to this diversity. Patients were categorized as grade 1 (mild), 2 (moderate) or 3 (severe) according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1–14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049). These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.
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