Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21
Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21
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DOI：
10.1093/hmg/6.4.641
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发表时间：
1997-04-01
影响因子：
3.5
通讯作者：
Sarfarazi, M
中科院分区：
文献类型：
--
作者：
Stoilov, I;Akarsu, AN;Sarfarazi, M
原发性先天性青光眼是一种常染色体隐性遗传性眼病，被认为是由眼前节发育缺陷引起的。此前，我们报道了该病的两个染色体位置，分别位于2p21(GLC3A)和1p36(GLC3B)。本研究描述了5个与GLC3A基因连锁的家系的人细胞色素P4501B1基因(CYP1B1)的可遗传突变，该基因已被定位在GLC3A候选区域内，并在小梁网络细胞中表达。以及影响外显子III 5‘端和邻近内含子区域的更大的缺失，所有这些都是移码突变，预计会移除对CYP1B1蛋白功能至关重要的结构域，因此，预计所有这些突变都会导致功能性零等位基因，在这些家族的受影响成员中检测到的突变在随机选择的正常个体的470条染色体中不存在，从而强烈表明CYP1B1是2p21上GLC3A位点的基因。
Primary congenital glaucoma (Buphthalmos) is an autosomal recessive eye disorder, postulated to result from developmental defects in the anterior eye segment, Previously, we reported two chromosomal locations for this condition on 2p21 (GLC3A) and 1p36 (GLC3B) respectively, In this study, heritable mutations of human cytochrome P4501B1 gene (CYP1B1) in affected individuals of five well-characterized families linked to the GLC3A locus are described, CYP1B1 gene has previously been mapped within the GLC3A candidate region and its expression in the trabecular meshwork cells has been demonstrated in this study, Three different homozygous mutations were identified and characterized: a 13 bp deletion in exon III; an insertion of a single cytosine base in exon II; and a larger deletion affecting the 5' end of exon III and the adjacent intronic region, All of these are frameshift mutations that are predicted to remove domains essential for the function of the CYP1B1 protein, Therefore, it is expected that all these mutations result in functional null alleles, The mutations detected in the affected members of these families were not present in 470 chromosomes from randomly selected normal individuals, thus strongly suggesting that CYP1B1 is the gene for the GLC3A locus on 2p21, The results are discussed in the context of the earlier hypothesis that 'drug-metabolizing' enzymes might modulate the processes of growth and differentiation by controlling the steady-state-levels of oxygenated growth-effector molecules.