Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities
Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities
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DOI：
10.1167/iovs.05-1095
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Traboulsi, EI
中科院分区：
文献类型：
--
作者：
Bidinost, C;Matsumoto, M;Traboulsi, EI
目的。PITX3基因编码一种同源框双核样转录因子，与人类显性白内障和眼前段间充质发育不全有关。在目前的研究中，检查了一个常染色体显性遗传性后极部白内障(PPC)和与该疾病相关的PITX3突变的家庭。还有两个PITX3突变纯合子的兄弟姐妹，他们患有小眼症和显著的神经损害。方法：对一个三基因定量的黎巴嫩家庭中的28名患病成员和14名未患病成员进行全基因组筛查、PITX3染色体10q25区域的连锁分析、单倍型分析和PITX3基因测序。结果：全基因组连锁分析显示，Q25区域10号染色体上theta=0.00处的Lod得分为3.56。单倍型和表型分析将该疾病基因座限制在标记D10S1239和D10S1268之间的10q25区域。候选基因PITX3映射到该区域。对PITX3基因进行测序发现，42个家系成员中有25个成员存在G杂合缺失突变。此外，来自近亲婚姻的两个兄弟姐妹被发现为缺失的纯合子。结论：这是人类PITX3纯合子突变的第一个报告。这些个体的表型突出了PITX3在眼睛和中枢神经系统(CNS)发育中的作用。
PURPOSE. The PITX3 gene, which codes for a homeobox bicoidlike transcription factor is responsible for dominant cataract and anterior segment mesenchymal dysgenesis in humans. In the current study, a family with autosomal dominant posterior polar cataract (PPC) and a PITX3 mutation that cosegregates with the disease was examined. Also studied were two siblings who were homozygous for the PITX3 mutation who had microphthalmia and significant neurologic impairment.METHODS. A genome-wide screen, linkage analysis in the PITX3 chromosomal region 10q25, haplotype analysis, and sequencing of the PITX3 gene were performed on 28 affected and 14 unaffected member of a three-gene ration Lebanese family.RESULTS. Genome-wide linkage analysis showed a lod score of 3.56 at theta = 0.00 on chromosome 10 at area q25. Analysis of the haplotypes and phenotypes confined the disease locus to a region on 10q25 between the markers D10S1239 and D10S1268. A candidate gene, PITX3, maps to that region. Sequencing of the PITX3 gene revealed a heterozygous G deletion mutation in 25 of the 42 family members. In addition, two siblings from a consanguineous marriage were found to be homozygous for the deletion.CONCLUSIONS. This is the first report of homozygous PITX3 mutations in humans. The phenotype in these individuals highlights the role of PITX3 in ocular and central nervous system (CNS) development.