An Alu repeat-mediated genomic GCNT2 deletion underlies congenital cataracts and adult i blood group
An Alu repeat-mediated genomic GCNT2 deletion underlies congenital cataracts and adult i blood group
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DOI：
10.1007/s00439-011-1062-1
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发表时间：
2012-02-01
期刊：
影响因子：
5.3
通讯作者：
Kubisch, Christian
中科院分区：
文献类型：
--
作者：
Borck, Guntram;Kakar, Naseebullah;Kubisch, Christian
我们在一个分离常染色体隐性遗传性先天性白内障的巴基斯坦血缘家庭中进行了纯合子定位，并确定了与染色体6p24上包含GCNT2基因的3.03 Mb基因座的连锁。GCNT2编码氨基葡萄糖(N-乙酰)转移酶2，这是一种负责形成I型血型抗原的酶。罕见的双等位基因GCNT2突变已被证明与先天性白内障和成人I型血型有关，使GCNT2成为观察到的表型的首要候选基因。事实上，我们确定了一种与白内障分离的纯合子缺失，该缺失包含GCNT2的1B、1C、2和3外显子。长程聚合酶链式反应和断点测序显示，在这个和第二个明显无关的分离先天性白内障的巴基斯坦家庭中，受影响的个体是相同的93kb缺失的纯合子。该缺失位于ALU家族两侧的Alu重复序列的两侧，微卫星基因分析表明，该缺失在两个家系中的出现是Alu-Alu重复序列介导的非同源重组或老创始人效应的产物。随后，我们发现两个家族中受白内障影响的个体都有成年的I型血型，而未受影响的个体的血型是I型，这是人群的绝大多数。由于GCNT2基因座富含短散布元件(正弦重复)，因此很容易发生基因组重排，该基因座的微缺失或微重复可能导致明显孤立的常染色体-隐性白内障的比例高于目前预期的比例。
We performed homozygosity mapping in a consanguineous Pakistani family segregating autosomal-recessive congenital cataracts and identified linkage to a 3.03 Mb locus on chromosome 6p24 containing the GCNT2 gene. GCNT2 encodes glucosaminyl (N-acetyl) transferase 2, an enzyme responsible for the formation of the blood group I antigen. Rare biallelic GCNT2 mutations have been shown to cause the association of congenital cataracts and the adult i blood group, making GCNT2 the prime candidate gene for the observed phenotype. Indeed, we identified a homozygous deletion segregating with cataracts that encompasses exons 1B, 1C, 2 and 3 of GCNT2. Long-range polymerase chain reaction and breakpoint sequencing revealed that affected individuals in this and in a second, apparently unrelated Pakistani family segregating congenital cataracts are homozygous for the same 93 kb deletion. The deletion is flanked by Alu repeats of the AluS family on both sides and microsatellite genotyping suggested that its occurrence in the two families was the product of recurrent Alu-Alu repeat-mediated nonhomologous recombinations or an old founder effect. Subsequently, we showed that cataract-affected individuals in both families have the adult i blood group, whereas unaffected individuals have blood group I as the vast majority of the population. Because the GCNT2 locus is rich in Short INterspersed Elements (SINE repeats) and thus likely prone to genomic rearrangements, microdeletions or microduplications at this locus might cause a larger than currently anticipated fraction of apparently isolated autosomal-recessive cataracts.