De Castro M, García-Planells J, Monrós E, Cañizares J, Vázquez-Manrique R, Vílchez J J, Urtasun M, Lucas M, Navarro G, Izquierdo G, Moltó M D, Palau F
Unitat de Genètica, Hospital Universitari La Fe, Valencia, Spain.
Hum Genet. 2000 Jan;106(1):86-92. doi: 10.1007/s004399900201.
Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozygous patients were identified. In four patients, a point mutation that predicts a truncated frataxin was detected. Three of them associated classic early-onset Friedreich's ataxia with an expanded GAA allele greater than 800 repeats. The other patient associated late-onset disease at the age of 29 years with a 350-GAA repeat expansion. In two patients manifesting the classical phenotype, no changes were observed by single-strand conformation polymorphism (SSCP) analysis. Linkage analysis in a family with two children affected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA repeat number in the expanded allele. Complete molecular definition in these patients is required for clinical diagnosis and genetic counseling.
弗里德赖希共济失调由FRDA基因突变引起，该基因编码frataxin，一种核编码的线粒体蛋白。大多数患者为FRDA基因内GAA三联体重复序列扩增的纯合子，但少数患者表现为点突变和GAA重复序列扩增的复合杂合性。我们分析了241例常染色体隐性或孤立性脊髓小脑共济失调患者队列的DNA样本，检测GAA三联体扩增情况。对GAA扩增杂合的患者筛查FRDA编码区内的点突变。分子分析包括单链构象多态性分析、直接测序以及与FRDA基因座侧翼标记的连锁分析。共鉴定出7例复合杂合患者。在4例患者中，检测到一个预测截短型frataxin的点突变。其中3例与经典的早发性弗里德赖希共济失调相关，其GAA等位基因扩增超过800次重复。另1例患者在29岁时出现迟发性疾病，GAA重复序列扩增为350次。在2例表现出典型表型的患者中，单链构象多态性（SSCP）分析未观察到变化。在一个有两个孩子患共济失调综合征的家庭中进行连锁分析，其中一个孩子GAA扩增呈杂合性，结果证实与FRDA基因座无连锁关系。复合杂合性弗里德赖希共济失调患者中的大多数点突变为无效突变。在本研究的患者中，临床表型似乎与扩增等位基因中的GAA重复次数有关。这些患者需要完整的分子定义以进行临床诊断和遗传咨询。
