Melki Rahma, Belmouden Ahmed, Brézin Antoine, Garchon Henri-Jean
INSERM U580, Hôpital Necker, Paris, France.
Hum Mutat. 2003 Aug;22(2):179. doi: 10.1002/humu.9165.
Primary open-angle glaucoma (POAG) is a prevalent optic neuropathy with complex genetics. A small number of patients carry a mutation in the coding region of the myocilin (MYOC) gene. The nature and the frequency of these mutations, however, vary substantially, notably with the age at onset and the ethnic origin of the patients. Here, we showed that denaturing high performance liquid chromatography (DHPLC) is an appropriate method for screening carriers of MYOC mutations. We have applied the method to a group of 237 POAG patients and 108 control subjects from France. Mutations were found in 17 (7.5%) patients and in none of the controls. A single mutation, Q368X (c.1102C>T), accounted for the majority (12/17) of these mutations, corresponding to a frequency of 5% among POAG patients, the highest ever reported for this mutation. Furthermore, analysis of allelic associations at closely linked microsatellite markers indicated that most, if not all, patients inherited Q368X from a same ancestor. Five other patients carried four distinct mutations, including N480K (c.1440C>A) (2 cases), I499F (c.1495A>T), G367R (c.1099G>A) and T438I (c.1313C>T), which is reported here for the first time. Altogether, MYOC mutations in French patients were associated with a significantly increased intraocular pressure at diagnosis. In addition, the age at diagnosis of patients with a mutation other than Q368X was significantly younger than that of Q368X carriers or of patients with a normal MYOC. Based on these observations, a screening strategy of MYOC mutations in French POAG patients is briefly outlined.
原发性开角型青光眼（POAG）是一种常见的、具有复杂遗传学特征的视神经病变。少数患者在肌纤蛋白（MYOC）基因的编码区存在突变。然而，这些突变的性质和频率差异很大，尤其与发病年龄和患者的种族起源有关。在此，我们表明变性高效液相色谱法（DHPLC）是筛查MYOC突变携带者的一种合适方法。我们已将该方法应用于一组来自法国的237例POAG患者和108例对照受试者。在17例（7.5%）患者中发现了突变，而对照受试者中未发现突变。单个突变Q368X（c.1102C>T）占这些突变的大多数（12/17），在POAG患者中的频率为5%，是该突变迄今报道的最高频率。此外，对紧密连锁微卫星标记的等位基因关联分析表明，大多数（如果不是全部）患者从同一个祖先遗传了Q368X。另外5例患者携带4种不同的突变，包括N480K（c.1440C>A）（2例）、I499F（c.1495A>T）、G367R（c.1099G>A）和T438I（c.1313C>T），后者在此首次报道。总体而言，法国患者中的MYOC突变与诊断时显著升高的眼压相关。此外，携带Q368X以外突变的患者的诊断年龄明显低于Q368X携带者或MYOC正常的患者。基于这些观察结果，简要概述了法国POAG患者中MYOC突变的筛查策略。
