Chavarria-Soley Gabriela, Michels-Rautenstrauss Karin, Pasutto Francesca, Flikier David, Flikier Paul, Cirak Sebahattin, Bejjani Bassem, Winters Daniel L, Lewis Richard A, Mardin Christian, Reis Andre, Rautenstrauss Bernd
Institute of Human Genetics, Friedrich-Alexander-University, Erlangen, Germany.
Mol Vis. 2006 May 22;12:523-31.
Mutations in the cytochrome P450 1B1 (CYP1B1) gene are a frequent cause of primary congenital glaucoma (PCG) in different ethnic groups. Cytochrome P450 proteins are monooxygenases, which catalyze many reactions involved in the metabolism of drugs as well as steroids and other lipids. The repeated occurence of several mutations in various ethnic groups raises the question if founder effects or mutation-prone sites in CYP1B1 are the cause for this observation.
A total of 30 individuals (26 PCG patients, three Rieger's anomaly patients, and one variant carrier), presenting 17 variants in CYP1B1 (15 mutations and two variations) were included in our study. We sequenced the entire genomic region of CYP1B1 and analyzed microsatellites flanking the gene in all individuals and constructed haplotypes for all variations using a combination of single nucleotide polymorphisms and microsatellites.
For the CYP1B1 genomic region, we identified five extended haplotypes associated with 17 variations. These haplotypes were complemented with microsatellite information from the region surrounding this gene. A total of eight CYP1B1 mutations were found more than once, each of them presenting one identical haplotype in different individuals. Six mutations were represented in different ethnic groups.
Our results confirm founder effects for most of CYP1B1 mutations. Most of these mutations must have occurred as unique events in the past.
细胞色素P450 1B1（CYP1B1）基因突变是不同种族原发性先天性青光眼（PCG）的常见病因。细胞色素P450蛋白是单加氧酶，可催化许多参与药物、类固醇及其他脂质代谢的反应。不同种族中多种突变的反复出现引发了一个问题，即CYP1B1中的奠基者效应或易突变位点是否是这一现象的原因。
本研究纳入了30名个体（26名PCG患者、3名里格尔异常患者和1名变异携带者），他们的CYP1B1基因存在17种变异（15种突变和2种变体）。我们对CYP1B1的整个基因组区域进行了测序，并分析了所有个体中该基因侧翼的微卫星，结合单核苷酸多态性和微卫星构建了所有变异的单倍型。
对于CYP1B1基因组区域，我们鉴定出了与17种变异相关的5种扩展单倍型。这些单倍型补充了该基因周围区域的微卫星信息。共发现8种CYP1B1突变不止出现一次，每种突变在不同个体中呈现相同的单倍型。6种突变出现在不同种族中。
我们的结果证实了大多数CYP1B1突变存在奠基者效应。这些突变中的大多数肯定是过去作为独特事件发生的。
