Mackey David A, Healey Danielle L, Fingert John H, Coote Michael A, Wong Tiffany L, Wilkinson Colleen H, McCartney Paul J, Rait Julian L, de Graaf A Pauline, Stone Edwin M, Craig Jamie E
Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia.
Arch Ophthalmol. 2003 Aug;121(8):1172-80. doi: 10.1001/archopht.121.8.1172.
To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met.
Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing.
From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean +/- SD age at diagnosis of 41.2 +/- 11.5 years, and a mean peak intraocular pressure of 31.7 +/- 9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype.
The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.
研究携带肌纤蛋白突变Thr377Met的澳大利亚家族中原发性开角型青光眼（POAG）的表型及年龄相关外显率。
横断面基因研究。从塔斯马尼亚青光眼遗传研究中连续超过2000例POAG病例以及澳大利亚各地转诊至该研究的青光眼家族中，确定了4个携带Thr377Met突变的无亲缘关系家系。对索引病例和可及的家庭成员进行青光眼体征检查，并通过单链构象多态性分析及后续直接测序确定是否存在GLC1A Thr377Met突变。
在4个携带Thr377Met突变的家系中，发现23例患有高眼压症（OHT）或POAG的个体，诊断时的平均年龄±标准差为41.2±11.5岁，平均眼压峰值为31.7±9.9 mmHg。另外对9名年龄超过18岁且尚未出现OHT或POAG体征的突变携带者进行了研究（这9人中6人年龄小于30岁）。鉴定出1例患有POAG但未携带Thr377Met突变的个体。对于Thr377Met携带者，30岁时OHT或POAG的年龄相关外显率为88%。4例索引病例中有3例有POAG家族史阳性。23例患有OHT或POAG的Thr377Met携带者中有13例（57%）接受了青光眼引流手术。尽管这些家族中的青光眼似乎与眼压有关，但有2例在眼压升高被检测到之前就出现了视盘杯状凹陷。1个家族来自英国，其单倍型背景与另外3个来自希腊或马其顿且共享一个共同单倍型的家族不同。
GLC1A Thr377Met突变与POAG相关，在所研究的家系中，与具有更常见的Gln368STOP突变的家系相比，发病年龄更小，眼压峰值更高。此外，携带Thr377Met突变的青光眼患者更有可能接受青光眼引流手术。
