Hewitt Alex W, Samples John R, Allingham R Rand, Järvelä Irma, Kitsos George, Krishnadas Subbaiah R, Richards Julia E, Lichter Paul R, Petersen Michael B, Sundaresan Periasamy, Wiggs Janey L, Mackey David A, Wirtz Mary K
Department of Ophthalmology, Flinders University, Adelaide, Australia.
Mol Vis. 2007 Mar 28;13:487-92.
The aim of this study was to determine if there is a common founder for the Thr377Met myocilin mutation in primary open angle glaucoma (POAG) families with various ethnic backgrounds.
Genomic DNA of 24 POAG-affected individuals from nine pedigrees with the Thr377Met mutation and 104 unaffected family members was genotyped with six microsatellite markers and four single nucleotide polymorphisms. The families were from Greece, India, Finland, the USA, and Australia. To assess the degree of linkage disequilibrium across MYOC in the general population we also investigated data generated from the HapMap consortium.
Three distinct haplotypes associated with the Thr377Met myocilin mutation were identified. The families from the USA and Greece, as well as the three Australian families originating from Greece and the former Yugoslavian Republic of Macedonia had one common haplotype. Interestingly, however, HapMap data suggest that linkage disequilibrium across MYOC was not strong.
The Thr377Met myocilin mutation has arisen at least three separate times. Evidence for genetic founder effects in this prevalent age-related, yet heterogeneous, disease has important implications for future gene identification strategies.
本研究旨在确定在具有不同种族背景的原发性开角型青光眼（POAG）家族中，377位苏氨酸突变为甲硫氨酸的肌纤蛋白突变是否存在共同的起源。
对来自9个家系的24位受POAG影响且带有377位苏氨酸突变为甲硫氨酸突变的个体以及104位未受影响的家庭成员的基因组DNA进行基因分型，使用6个微卫星标记和4个单核苷酸多态性。这些家系来自希腊、印度、芬兰、美国和澳大利亚。为了评估一般人群中MYOC基因座连锁不平衡的程度，我们还研究了国际人类基因组单体型图协会（HapMap）产生的数据。
鉴定出与377位苏氨酸突变为甲硫氨酸的肌纤蛋白突变相关的三种不同单倍型。来自美国和希腊的家系，以及源自希腊和前南斯拉夫的马其顿共和国的三个澳大利亚家系具有一种共同的单倍型。然而，有趣的是，HapMap数据表明MYOC基因座的连锁不平衡并不强烈。
377位苏氨酸突变为甲硫氨酸的肌纤蛋白突变至少出现了三次。在这种常见的、与年龄相关但异质性的疾病中存在遗传奠基者效应的证据，对未来的基因鉴定策略具有重要意义。
