Frataxin gene point mutations in Italian Friedreich ataxia patients
Frataxin gene point mutations in Italian Friedreich ataxia patients
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DOI：
10.1007/s10048-007-0101-5
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发表时间：
2007-11-01
期刊：
影响因子：
2.2
通讯作者：
Taroni, Franco
中科院分区：
文献类型：
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作者：
Gellera, Cinzia;Castellotti, Barbara;Taroni, Franco
Friedreich共济失调(Friedreich ataxia，FRDA)与FXN基因(9q13-21)第一内含子的GAA-三核苷酸重复扩增有关，该基因编码一种名为frataxin的210个氨基酸的蛋白质。超过95%的患者在两个等位基因上都有90-1300个重复扩增的纯合子。其余的患者已经被证明是一个等位基因上的GAA扩大和另一个等位基因上的微突变的复合杂合子。Frataxin信使RNA(MRNA)和蛋白质的减少被发现与较小的GAA重复等位基因的大小成比例。我们报道了一项对12个典型FRDA患者的临床和分子研究，在这些家系中，一个等位基因上的GAA扩展是杂合的。对FXN基因的序列分析可以在每个杂合子患者中鉴定出第二个致病突变，这使其成为迄今报道的第二大FRDA复合杂合子系列。我们已经确定了七个突变，其中四个是新的。5名患者携带错义突变，而8名患者携带零(移码或无义)突变。来自6个复合杂合子患者的淋巴母细胞系中Frataxin水平的定量显示，残留蛋白水平与发病年龄(r=0.82，p<；0.05)或GAA扩张期(r=-0.76，p<；0.1)有统计学意义的相关性。在杂合子为空等位基因的患者组中，GAA扩增的大小与发病年龄之间存在很强的相关性(r=-0.94，p<；0.01)，从而支持了患者细胞中Frataxin的残留功能完全来自于扩增的等位基因的假设。
Friedreich ataxia (FRDA) is associated with a GAA-trinucleotide-repeat expansion in the first intron of the FXN gene (9q13-21), which encodes a 210-amino-acid protein named frataxin. More than 95% of patients are homozygous for 90-1,300 repeat expansion on both alleles. The remaining patients have been shown to be compound heterozygous for a GAA expansion on one allele and a micromutation on the other. The reduction of both frataxin messenger RNA (mRNA) and protein was found to be proportional to the size of the smaller GAA repeat allele. We report a clinical and molecular study of 12 families in which classical FRDA patients were heterozygous for a GAA expansion on one allele. Sequence analysis of the FXN gene allowed the identification of the second disease-causing mutation in each heterozygous patient, which makes this the second largest series of FRDA compound heterozygotes reported thus far. We have identified seven mutations, four of which are novel. Five patients carried missense mutations, whereas eight patients carried null (frameshift or nonsense) mutations. Quantitation of frataxin levels in lymphoblastoid cell lines derived from six compound heterozygous patients showed a statistically significant correlation of residual protein levels with the age at onset (r=0.82, p < 0.05) or the GAA expansion (r=-0.76, p < 0.1). In the group of patients heterozygous for a null allele, a strong (r=-0.94, p < 0.01) correlation was observed between the size of GAA expansion and the age at onset, thus lending support to the hypothesis that the residual function of frataxin in patients' cells derive exclusively from the expanded allele.