Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus
Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus
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DOI：
10.1093/hmg/9.3.367
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发表时间：
2000-02-12
影响因子：
3.5
通讯作者：
Lupski, JR
中科院分区：
文献类型：
--
作者：
Bejjani, BA;Stockton, DW;Lupski, JR
原发性先天性青光眼（PCG）是一种常染色体隐性遗传疾病，与前房中未知的发育缺陷相关。最近，我们报道了25个分离PCG的沙特家庭中细胞色素P4501B1基因CYP1B1的三种不同突变。在这份报告中，我们分析了另外37个家庭，并证实了最初的发现，即细胞色素P4501B1降低。通过对CYP1B1基因外显子直接测序，分析了突变和基因内单核苷酸多态性（SNP），共发现8种不同的突变：G61E、R469W和D374N是最常见的Saudi突变，分别占PCG染色体的72%、12%和7%。另外五个纯合突变（两个缺失和三个错义突变）被检测到，每个在一个单一的家庭。来自5个家庭的受影响个体没有CYP1B1编码突变，每个家庭都有独特的SNP谱。在一个单一的基因中，在四个不同的单倍型，八个不同的突变的鉴定，表明在沙特阿拉伯的CYP1B1的多个突变的相对较新的发生。这些数据表明，沙特人口中PCG表型的突变率降低，因为22个家庭中的40个明显未受影响的个体与其受影响的兄弟姐妹具有相同的突变和单倍型。两个人随后被诊断为青光眼，另外两个人有异常的眼部发现，这与轻度青光眼一致。对这22种激酶的分析表明，存在一个与CYP1B1基因无关的显性修饰基因位点。连锁和Southern分析排除了三个候选修饰基因座。
Primary congenital glaucoma (PCG) is an autosomal recessive disorder associated with unknown developmental defect(s) in the anterior chamber. Recently, we reported three distinct mutations in CYP1B1, the gene for cytochrome P4501B1, in 25 Saudi families segregating PCG, For this report, we analyzed 37 additional families and confirmed the initial finding of decreased penetrance. Mutations and intragenic single-nucleotide polymorphisms (SNPs) were also analyzed from direct sequencing of all CYP1B1 coding exons, Eight distinct mutations were identified: G61E, R469W and D374N, the most common Saudi mutations, account for 72, 12 and 7%, respectively, of all the PCG chromosomes. Five additional homozygous mutations (two deletions and three missense mutations) were detected, each in a single family. Affected individuals from five families had no CYP1B1 coding mutations, and each family had a unique SNP profile. The identification of eight distinct mutations in a single gene, on four distinct haplotypes, suggests a relatively recent occurrence of multiple mutations in CYP1B1 in Saudi Arabia. These data demonstrate decreased penetrance of the PCG phenotype in the Saudi population, because 40 apparently unaffected individuals in 22 families have mutations and haplotypes identical to their affected siblings. Two individuals were subsequently diagnosed with glaucoma and two others had abnormal ocular findings that are consistent with milder forms of glaucoma. Analysis of these 22 kindreds suggests the presence of a dominant modifier locus that is not linked genetically to CYP1B1. Linkage and Southern analyses excluded three candidate modifier loci.