原发性开角型青光眼家系一新的myocilin基因突变

A novel mutation in the myocilin gene identified in a Chinese primary open angle glauconm family

目的探讨一个中国人原发性开角型青光眼（primary open angle glaucoma,POAG）家系的my-ocilin基因缺陷。方法对一个5代POAG大家系进行全面的临床检查后,用聚合酶链反应扩增家系成员myocilin基因的所有外显子以及相邻部分内含子,对其产物直接测序。结果家系的遗传方式符合常染色体显性遗传。确诊年龄在26～59岁之间。在所有青光眼患者,可疑者以及4例尚未出现明显青光眼体征的家系成员发现携带myocilin基因T455K突变。无该突变的家系成员中无POAG患者及可疑者。突变位于myocilin蛋白C-末端非常保守的氨基酸残基。结论T455K突变是中国人所特有的新的致病性myocilin基因突变。突变的临床表型为混合发病年龄型POAG且具有很高的外显率。这个新基因突变的发现证实中国人的致病性myocilin基因突变类型与其他种族不同。

Objective To determine the possible myocihn molecular genetic defect underlying POAG in China and to identify the pathogenic mutation causing the disease. Methods The majority of 1 branch of a large Chinese POAG family were personally examined by two senior ophthalmologists. The diagnoses were made by both doctors according to the signs of elevated intraecular pressure, glaucomatous optic neuropathy and glaucomatous visual field defect. All coding sequences of the myecilin gene plus the flanking sites were amplified by polymerase chain reaction （PCR） using genomic DNA from all examined family members followed by sequencing of the PCR products. One hundred normal control subjects were screened by single strand confirmational polymorphism analysis for the mutation. Results This Chinese pedigree exhibited autosomal dominant mode of inheritance. The onset age ranged from 26 to 59 years. A novel diseasecausing missense mutation T455K in the third exon of the myecilin gene was identified in all affected family members, all glaucoma suspects and 4 individuals who have not shown apparently signs of glaucoma. None of the subjects without the mutation had glaucoma. Affected individuals with the T455K mutation showed variable onset between 26 and 59 years of age. Filtering surgery was performed on all of 7 affected family members. The T455K mutation in myecilin gene was not found in the normal controls. A previously reported polymorphism 1VS2 ＋ 35（A 〉 G）was detected in 4 individuals. Condusion The novel myecihn sequence alteration T455K that is highly associated with the development of glaucoma and locates in a very conserved residue is proven to be a disease-causing missence mutation. All affected individuals and all POAG suspects in this family are identified to have this mutation. The mutation in this family is associated with a phenotype characterized by mix-onset open angle glaucoma and associated with a high penetrance. It is important for the mutation screening and periodical checkups of presymptomatic individuals belonging to the family of a POAG patient with T455K mutation.