Genome-Wide Homozygosity Mapping in Families with Leber Congenital Amaurosis Identifies Mutations in AIPL1 and RDH12 Genes
Genome-Wide Homozygosity Mapping in Families with Leber Congenital Amaurosis Identifies Mutations in AIPL1 and RDH12 Genes
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DOI：
10.1089/dna.2014.2554
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发表时间：
2014-12-01
影响因子：
3.1
通讯作者：
Ozgul, Riza Koksal
中科院分区：
文献类型：
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作者：
Yucel-Yilmaz, Didem;Tarlan, Bercin;Ozgul, Riza Koksal
Leber先天性黑蒙（LCA）在生命早期导致严重的视力障碍和失明。几个基因的突变等位基因在不同的途径，其中所有的正常视网膜功能的关键作用，参与LCA的发展。本研究的目的是使用全基因组基因分型，以确定在两个土耳其家庭的LCA致病位点。进行全基因组基因分型和单倍型分析，用于LCA家系突变筛查的候选基因的优先排序。通过纯合性作图从家族中获得的鉴定的信息性关键染色体区域被搜索以寻找任何LCA致病基因的重叠。评估具有鉴定的突变的患者的相应临床表型。在这项研究中，两个家庭被证明与两个不同的LCA位点，包括视黄醇脱氢酶12（RDH12）和芳基烃相互作用蛋白样1（AIPL1）基因。突变筛查显示AIPL1基因中存在新的p.Gln141* 突变，RDH12基因中存在先前描述的p.Thr49Met纯合突变。我们的RDH12突变患者有明显的黄斑缺损体征，AIPL1突变患者发生小眼症和严重的广泛视网膜色素上皮萎缩，与以前报道的病例相反。目前很明显，突变筛查需要在至少18个已知与LCA相关的基因中进行。因此，纯合性图谱是改善LCA分子诊断的一种替代技术，LCA是一组导致视网膜变性的遗传和临床异质性疾病。在已知基因中没有突变的患者可以通过使用下一代测序来进一步分析。
Leber congenital amaurosis (LCA) causes severe visual impairment and blindness very early in life. Mutant alleles of several genes acting in different pathways, of which all have critical roles for normal retinal function, were involved in LCA development. The purpose of this study was to use genome-wide genotyping to identify LCA-causing loci in two Turkish families. Genome-wide genotyping and haplotype analysis were performed for prioritization of candidate genes for mutation screening in families with LCA. Identified informative critical choromosomal regions obtained by homozygosity mapping from the families were searched for overlapping of any LCA causative genes. Corresponding clinical phenotypes of the patients with identified mutations were evaluated. In this study, two families were shown to be linked to two different LCA loci covering retinol dehydrogenase 12 (RDH12) and aryl-hydrocarbon-interacting protein-like1 (AIPL1) genes. Mutation screening revealed a novel p.Gln141* mutation in the AIPL1 gene and a previously described p.Thr49Met mutation in the RDH12 gene in a homozygous state. Our patients with the RDH12 mutation had the distinct macular coloboma sign, and the patient with the AIPL1 mutation developed microphthalmia and severe widespread retinal pigment epithelial atrophy, in contrast to previously reported cases. It is currently evident that mutation screening needs to be done in at least 18 genes known to be associated with LCA. Thus, homozygosity mapping is an alternative technique to improve the molecular diagnosis in LCA, which is a group of genetically and clinically heterogeneous diseases causing retinal degeneration. The patients without mutation in known genes may further be analyzed by using next-generation sequencing.