Cossée M, Dürr A, Schmitt M, Dahl N, Trouillas P, Allinson P, Kostrzewa M, Nivelon-Chevallier A, Gustavson K H, Kohlschütter A, Müller U, Mandel J L, Brice A, Koenig M, Cavalcanti F, Tammaro A, De Michele G, Filla A, Cocozza S, Labuda M, Montermini L, Poirier J, Pandolfo M
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Hôpitaux Universitaires de Strasbourg, Illkirch, France.
Ann Neurol. 1999 Feb;45(2):200-6. doi: 10.1002/1531-8249(199902)45:2<200::aid-ana10>3.0.co;2-u.
Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.
弗里德赖希共济失调是最常见的遗传性共济失调。96%的患者在铁调素基因的第一个内含子中存在GAA三核苷酸重复扩增的纯合子。其余病例为GAA扩增和铁调素点突变的复合杂合子。我们在此报告鉴定出10种新的铁调素点突变，并在另外两个家系中检测到一种先前描述的突变（G130V）。大多数截短突变位于外显子1。所有错义突变均位于编码成熟铁调素蛋白的最后三个外显子中。将25例已鉴定铁调素点突变患者的临床特征与196例GAA扩增纯合子患者的临床特征进行了比较。截短突变和成熟铁调素羧基末端一半的错义突变导致了相似的表型，这表明它们导致了相当的功能丧失。相比之下，成熟铁调素氨基末端一半中仅有的两个错义突变（D122Y和G130V）导致非典型且较轻的临床表现（早发性痉挛性步态，疾病进展缓慢，无构音障碍，腱反射保留或亢进，轻度或无小脑共济失调），这表明它们仅部分影响铁调素功能。复合杂合子中视盘苍白的发生率高于扩增纯合子，这可能与扩增等位基因产生的正常铁调素残留水平极低有关。
