Novel mutations in the OPA1 gene and associated clinical features in Japanese patients with optic atrophy
Novel mutations in the OPA1 gene and associated clinical features in Japanese patients with optic atrophy
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DOI：
10.1016/j.ophtha.2005.10.054
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发表时间：
2006-03-01
期刊：
影响因子：
13.7
通讯作者：
Terasaki, H
中科院分区：
文献类型：
--
作者：
Nakamura, M;Lin, J;Terasaki, H
目的：常染色体显性视神经萎缩（ADOA）的特征是对称性双侧视神经萎缩，伴有矫正视力（VA）降低，中央或中央暗瘤，以及色觉障碍。该病具有遗传异质性，目前已确定OPA1基因为唯一致病基因。本研究的目的是鉴定和报告日本ADOA患者的OPA1基因突变，并描述与突变相关的临床特征。设计：分子遗传学研究和观察性病例报告。参与者：9个无亲缘关系的视神经萎缩的日本家庭和8个孤立的视神经萎缩病例。方法：提取外周血白细胞的基因组DNA，直接测序含有开放阅读框的所有外显子和侧翼内含子剪接位点。进行了完整的眼科检查。主要观察指标：OPA1基因直接测序及VA、视野、色觉、椎间盘外观等临床评价。结果：在OPA1基因中检测到10个不同的杂合突变，其中6个为新突变。所鉴定的突变包括5个缺失/插入（c.2061delA, c.2098_2103delCTTAAA, c.2538insT, c.2591 insC和c.2708_2711delTTAG）， 4个无义突变(c.112C > T [p。[j]，李建平，李建平，等。[j], [j], [j]。[j]; [c]; [c]；R905X])和1个错义突变（c.1635C > A [p.S545R]）。在白种人中最常见的突变（c.2708_2711 delTTAG）在3个不相关的家族中被发现，提示它是一个突变热点。我们在9例家族性视神经萎缩病例中的8例检测到OPA1突变，在8例中有4例检测到OPA1突变，这些突变最初被认为是来自患者家族史的散发性病例。对2例散发先证家族成员的检查发现，存在其他家族成员携带OPA1突变，表型非常轻微或在正常范围内。这表明，ADOA患者有时似乎是散发的，因为表型的广泛变化，或者，ADOA的低外显率。结论：OPA1基因突变是日本家族性ADOA发病的主要原因。在日本人群中，偶发的视神经萎缩病例可能是由OPA1突变引起的。分子遗传学检查有助于确定某些视神经萎缩病例的遗传模式。
Purpose: Autosomal dominant optic atrophy (ADOA) is characterized by symmetrical bilateral optic atrophy associated with reduced corrected visual acuity (VA), central or centrocecal scotoma, and color vision disturbances. The disease is genetically heterogeneous, and the OPA1 gene has been identified as the only causative gene. The aims of this study were to identify and report mutations in the OPA1 gene in Japanese patients with ADOA and to describe the clinical features associated with the mutations.Design: Molecular genetic study and observational case reports.Participants: Nine unrelated Japanese families with optic atrophy and 8 isolated cases of optic atrophy.Methods: Genomic DNA was extracted from peripheral leukocytes, and all exons containing the open reading frame of the OPA1 gene and the flanking intron splice sites were sequenced directly. Complete ophthalmologic examinations were performed.Main Outcome Measures: Direct sequencing of the OPA1 gene and clinical evaluations including VA, visual field, color vision, and disc appearance.Results: Ten different heterozygous mutations, including 6 novel mutations, were detected in the OPA1 gene. The identified mutations included 5 deletions/insertions (c.2061delA, c.2098_2103delCTTAAA, c.2538insT, c.2591 insC, and c.2708_2711delTTAG), 4 nonsense mutations (c.112C > T [p.R38X], c.181C > T [p.061X], c.946A > T [p.R316X], and c.2713C > T [p.R905X]), and 1 missense mutation (c.1635C > A [p.S545R]). The most common mutation in Caucasians (c.2708_2711 delTTAG) was found in 3 unrelated families, suggesting that it is a mutational hot spot. We detected an OPA1 mutation in 8 of 9 familial cases of optic atrophy and in 4 of 8 cases that were initially considered to be sporadic from the patients' family histories. Examinations of family members of 2 sporadic probands revealed the existence of other family members with the OPA1 mutations whose phenotype was very mild or within normal limits. This indicates that patients with ADOA sometimes seem to be sporadic because of the extensive variation in the phenotype or, alternatively, a low penetrance of ADOA.Conclusions: OPA1 gene mutations are causative in most familial cases of ADOA in Japanese. Sporadic cases of optic atrophy frequently may be caused by OPA1 mutations in the Japanese population. Molecular genetic examinations are useful in determining the hereditary patterns in some cases of optic atrophy.