CYP1B1基因的分子分析：原发性先天性青光眼患者中新发截短突变的鉴定

Messina-Baas O M, González-Huerta L M, Chima-Galán C, Kofman-Alfaro S H, Rivera-Vega M R, Babayán-Mena I, Cuevas-Covarrubias S A

Servicio de Oftalmología, Hospital General de México, Facultad de Medicina, UNAM, México, D.F., México.

Ophthalmic Res. 2007;39(1):17-23. doi: 10.1159/000097902. Epub 2006 Dec 11.

BACKGROUND

Mutations and polymorphisms have been identified in the CYP1B1 gene; while mutations that affect the conserved core structures of cytochrome P4501B1 result in primary congenital glaucoma (PCG), mutations in other regions hold the potential to define differences in estrogen metabolism. In the present study, we analyzed the CYP1B1 gene in Mexican patients with PCG and described four novel mutations.

MATERIALS AND METHODS

The sample included 12 nonrelated cases with PCG. Analysis of coding regions of the CYP1B1 gene was performed through PCR and DNA sequencing analysis from genomic DNA.

RESULTS AND DISCUSSION

Molecular analysis of the CYP1B1 gene showed the following molecular defects: (1) a novel single-base pair deletion within codon 370 (1454delC) that produces a substitution of leucine instead of proline and a premature stop codon 57 amino acids after the last original amino acid; this family also harbored a novel polymorphic variant of the cytochrome P4501B1 with six single-nucleotide polymorphisms (142C-->G; 355G-->T; 729G-->C; 4326C-->G; 4360C-->G and 4379C-->T); (2) a novel single-base pair deletion within codon 277 (1176delT) that results in a premature stop codon; (3) a novel single-base pair deletion within codon 179 (880delG) that produces a substitution of arginine instead of alanine and a premature stop codon 17 amino acids downstream from the last original amino acid, and (4) a duplication (or insertion) of ten base pairs within codon 404 (1556dupATGCCACCAC) that results in a premature stop codon 26 amino acids after the last original amino acid. We also observed in 2 nonrelated patients a deletion of 13 bp (1410_1422delGAGTGCAGGCAGA) previously reported for other populations.

CONCLUSION

We reported four novel mutations and a novel polymorphic variant in the CYP1B1 gene in PCG in the Mexican population; it has important implications in diagnosis and genetic counseling.

背景

CYP1B1基因中已鉴定出突变和多态性；影响细胞色素P4501B1保守核心结构的突变会导致原发性先天性青光眼（PCG），而其他区域的突变有可能确定雌激素代谢的差异。在本研究中，我们分析了墨西哥PCG患者的CYP1B1基因，并描述了四个新的突变。

材料与方法

样本包括12例无亲缘关系的PCG病例。通过PCR和基因组DNA的DNA测序分析对CYP1B1基因的编码区进行分析。

结果与讨论

CYP1B1基因的分子分析显示出以下分子缺陷：（1）密码子370内一个新的单碱基对缺失（1454delC），导致亮氨酸取代脯氨酸，并且在最后一个原始氨基酸后57个氨基酸处出现过早的终止密码子；该家族还存在细胞色素P4501B1的一个新的多态性变体，具有六个单核苷酸多态性（142C→G；355G→T；729G→C；4326C→G；4360C→G和4379C→T）；（2）密码子277内一个新的单碱基对缺失（1176delT），导致过早的终止密码子；（3）密码子179内一个新的单碱基对缺失（880delG），导致精氨酸取代丙氨酸，并且在最后一个原始氨基酸下游17个氨基酸处出现过早的终止密码子，以及（4）密码子404内十个碱基对的重复（或插入）（1556dupATGCCACCAC），导致在最后一个原始氨基酸后26个氨基酸处出现过早的终止密码子。我们还在2例无亲缘关系的患者中观察到先前在其他人群中报道的13bp缺失（1410_1422delGAGTGCAGGCAGA）。