Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1
Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1
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DOI：
10.1093/hmg/ddi068
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发表时间：
2005-03-15
影响因子：
3.5
通讯作者：
Sarfarazi, M
中科院分区：
文献类型：
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作者：
Monemi, S;Spaeth, G;Sarfarazi, M
在几乎每个国家，青光眼都是导致失明的主要原因。开发一种准确的诊断测试来检测处于危险中的个体的症状前状态是对这种情况的迫切要求。在此，我们报道了一个新的成人起病的原发性开角型青光眼(POAG)基因定位于5q22.1(GLC1G)，并鉴定了其缺陷基因。对GLC1G关键区(类似于D5S1466和D5S2051之间的2Mb)的7个候选基因进行突变筛查，发现WDR36(WD40-Repeat 36)基因只有一个显著变化。该突变(即D658G)在我们的第一个GLC1G连锁家系的所有受影响成员中分离出来，但在476条正常对照染色体中缺失。在130个POAG家系中进一步筛查WDR36发现了24个DNA变异。总体而言，在17例(5.02-6.92%)无关的POAG患者中，发现了四个突变(N355S、A449T、R529Q和D658G)，其中11例患有高血压，6例患有低压性青光眼。这些突变在至少200条正常对照染色体中是不存在的，而且它们在小鼠、大鼠、狗、黑猩猩和人类的WDR36同源基因之间是保守的。WDR36是一个新的基因，有23个外显子，编码951个氨基酸，是一个具有多个G-βWD40重复序列的蛋白质。经Northern印迹分析，在人的心脏、胎盘、肝脏、骨骼肌、肾脏和胰腺中观察到两种不同的转录产物，分别为5.9和2.5kb。RT-PCR检测WDR36基因在晶状体、虹膜、巩膜、睫状肌、睫状体、小梁网、视网膜和视神经中的表达。在小鼠中，两个3.5kb和2.9kb的转录本显示了与人类相似的表达模式。在7天、11天、15天和17天的发育中的小鼠胚胎中检测到了mRNA的表达。综上所述，WDR36是位于GLC1G基因座的一个新的成人型POAG的致病基因。特殊的眼部表现和观察到的突变与WDR36在高压性和低压性青光眼病因中的作用一致。
Glaucoma is a leading cause of blindness in virtually every country. Development of an accurate diagnostic test for presymptomatic detection of individuals at risk is an urgent requisition for this condition. Herein, we report mapping of a new adult-onset primary open-angle glaucoma (POAG) locus on 5q22.1 ( GLC1G) and identification of its defective gene. Mutation screening of seven candidate genes from the GLC1G critical region ( similar to 2 Mb between D5S1466 and D5S2051) identified only one significant alteration in the WDR36 (WD40- repeat 36) gene. This mutation (i.e. D658G) was segregated in all affected members of our first GLC1G- linked family but it was absent in 476 normal control chromosomes. Further screening of WDR36 in a total of 130 POAG families revealed 24 DNA variations. Overall, four mutations ( N355S, A449T, R529Q and D658G) were identified in 17 (5.02 - 6.92%) unrelated POAG subjects, 11 with high-pressure and six with low-pressure glaucoma. These mutations were absent in a minimum of 200 normal control chromosomes and, further they were conserved between WDR36 orthologues in mouse, rat, dog, chimp and human. WDR36 is a novel gene with 23 exons, which encodes for 951 amino acids and a protein with multiple G-beta WD40 repeats. By northern blotting, two distinct mRNA transcripts of 5.9 and 2.5 kb were observed in human heart, placenta, liver, skeletal muscle, kidney and pancreas. WDR36 gene expression in lens, iris, sclera, ciliary muscles, ciliary body, trabecular meshwork, retina and optic nerve were established by RT-PCR. In mouse, two transcripts of 3.5 and 2.9 kb showed analogous expression patterns to human. mRNA expressions were detected in 7-, 11-, 15- and 17- day-old developing mouse embryos. In summary, WDR36 is a novel causative gene for adult-onset POAG at the GLC1G locus. Specific ocular expressions and observed mutations are consistent with WDR36 role in etiology of both high- and low- pressure glaucoma.