Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy
Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy
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DOI：
10.1136/jmg.2008.062570
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发表时间：
2009-02-01
影响因子：
4
通讯作者：
Wissinger, B.
中科院分区：
文献类型：
--
作者：
Fuhrmann, N.;Alavi, M. V.;Wissinger, B.
前言：常染色体显性遗传性视神经萎缩(ADOA)被认为是最常见的遗传性视神经病变。尽管遗传连锁研究表明，染色体3q28-q29上的OPA1基因座是迄今为止最常见的基因座，但以前的筛查研究--基于编码外显子的测序--只在32-70%的ADOA患者中发现了OPA1突变。因此，我们假设在以前的筛查方法中仍未发现的较大的缺失或重复可能是ADOA中OPA1突变的主要原因。方法：通过多重连接探针扩增(MLPA)方法分析42例独立的ADOA患者OPA1基因重排的存在。通过长距离聚合酶链式反应(PCR)和断点测序或通过侧翼微卫星标记的杂合性丢失分析来确认缺失或重复。结果：42例患者中有8例发生了基因组重排，包括外显子9和外显子24的单个外显子缺失，外显子1-5的缺失，OPA1基因的两个不同缺失，以及外显子7-9的重复。患者的表型具有很高的变异性，与OPA1点突变患者相似。讨论：我们的研究结果表明，OPA1基因位点的大基因组异常在ADOA患者中非常常见，并对ADOA患者OPA1突变的谱和发生率有很大贡献。这进一步强化了单倍体功能不全是OPA1相关ADOA的主要发病机制的假说。
Introduction: Autosomal dominant optic atrophy (ADOA) is considered as the most common form of hereditary optic neuropathy. Although genetic linkage studies point to the OPA1 locus on chromosome 3q28-q29 as by far the most common gene locus, previous screening studies-based on sequencing of the coding exons-detected OPA1 mutations in only 32-70% of ADOA patients. We therefore hypothesised that larger deletions or duplications that remained undetected in previous screening approaches may substantially contribute to the prevalence of OPA1 mutations in ADOA.Methods: 42 independent ADOA patients were analysed for the presence of genomic rearrangements in OPA1 by means of multiplex ligation probe amplification (MLPA). Deletions or duplications were confirmed either by long distance polymerase chain reaction (PCR) and breakpoint sequencing or loss of heterozygosity analyses with flanking microsatellite markers. Patients underwent ophthalmological examination including visual acuity, colour vision testings, perimetry and funduscopy.Results: We identified genomic rearrangements in 8 of 42 patients, including single exon deletions of exon 9 and exon 24, respectively, a deletion of exons 1-5, two different deletions of the complete OPA1 gene as well as a duplication of the exons 7-9, with the latter being present in three unrelated families. Patients' phenotypes were highly variable, similar to patients with point mutation in OPA1.Discussion: Our findings show that gross genomic aberrations at the OPA1 gene locus are frequent in ADOA and substantially contribute to the spectrum and prevalence of OPA1 mutations in ADOA patients. They further strengthen the hypothesis that haploinsufficiency is a major pathomechanism in OPA1 associated ADOA.