OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance
OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance
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DOI：
10.1093/hmg/10.13.1359
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发表时间：
2001-06-15
影响因子：
3.5
通讯作者：
Wissinger, B
中科院分区：
文献类型：
--
作者：
Pesch, UEA;Leo-Kottler, B;Wissinger, B
我们和其他人最近发现，编码动力蛋白相关线粒体蛋白的OPA1基因突变会导致与染色体3q28-q29连锁的常染色体显性遗传性视神经萎缩(ADOA)。在这里，我们报告了在78个独立的ADOA家系样本中OPA1基因的筛查。在25例患者中发现了OPA1突变(检出率为32.1%)，其中包括16个新突变。我们成功地从3例患者的白细胞RNA中扩增了OPA1基因，发现携带Arg366Stop突变的转录本与来自正常染色体的转录本相比显著减少。对ADOA中OPA1突变分布的分析表明，大多数错义突变聚集在假定的GTPase结构域，并且有大多数突变导致提前翻译终止。这些观察结果支持单倍体功能不全可能是ADOA的主要发病机制的观点。此外，我们鉴定了一名ADOA患者，他是两个OPA1错义突变的复合杂合子。这位患者比她单纯的杂合子父母和兄弟姐妹受到的影响要严重得多，这一事实表明，至少这些OPA1等位基因表现为半显性，而不是纯粹的显性。临床检查显示，在携带OPA1突变的患者中，疾病表现有相当大的变异性，与突变的位置或类型没有严格的相关性。
We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28-q29. Here we report screening of the OPA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were identified in 25 patients (detection rate 32.1%) including 16 novel mutations. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mutation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA revealed that most missense mutations cluster within the putative GTPase domain, and that there is a preponderance of mutations, which result in premature translation termination. These observations support the notion that haploinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affected than her simple heterozygotic parents and siblings implies that at least these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation.