Stevanin Giovanni, Bouslam Naima, Thobois Stéphane, Azzedine Hamid, Ravaux Lucas, Boland Anne, Schalling Martin, Broussolle Emmanuel, Dürr Alexandra, Brice Alexis
INSERM U289, Federative Institute for Neuroscience Research (IFR-70), Paris.
Ann Neurol. 2004 Jan;55(1):97-104. doi: 10.1002/ana.10798.
Autosomal dominant cerebellar ataxias constitute one of the most clinically, neuropathologically, and genetically heterogeneous groups of neurodegenerative disorders. Approximately 50 to 80% of the families carry mutations in genes known to be implicated in spinocerebellar ataxias (SCAs). Numerous loci (SCAn) also have been mapped, often in single families, but the responsible genes have not yet been identified. This suggests further genetic heterogeneity. We have ascertained 18 subjects from a large French family in which cerebellar ataxia and prominent sensory neuropathy segregated as a dominant trait. Intrafamilial variability was high regarding age at onset (17 months to 39 years), severity, and the clinical picture that ranged from pure sensory neuropathy with little cerebellar involvement to a Friedreich's ataxia-like phenotype. After excluding known genes/loci responsible for SCA and hereditary sensory neuropathies, we detected linkage with chromosome 2p markers in a genomewide screen. We designated this new locus SCA25 after testing of 16 additional markers. Maximum two-point logarithm of odds scores of 3.15 and 3.10 were obtained at D2S2378 and D2S2734, respectively. Haplotype analysis defined a critical 12.6cM region of 15Mb between D2S2174 and D2S2736. No linkage to this locus was found in four other families. This interval contains several genes that could be responsible for the disease. One of these genes, CRIPT, encodes a postsynaptic protein, but no mutations were found by direct sequencing, excluding its responsibility in the disease. CAG repeat expansions often are involved in SCA pathogenesis, but no pathological expansions were found at the protein or at the DNA level using the 1C2 antibody and the repeat expansion detection method, respectively. The gene responsible for SCA25 remains to be identified.
常染色体显性遗传性小脑共济失调是临床上、神经病理学上和遗传学上最具异质性的神经退行性疾病群体之一。大约50%至80%的家系携带已知与脊髓小脑共济失调（SCA）相关的基因突变。许多基因座（SCAn）也已被定位，通常是在单个家系中，但相关基因尚未确定。这表明存在进一步的遗传异质性。我们从一个法国家系中确定了18名受试者，该家系中，小脑共济失调和明显的感觉神经病变以显性性状分离。家系内变异性在发病年龄（17个月至39岁）、严重程度以及临床表现方面都很高，临床表现范围从几乎没有小脑受累的纯感觉神经病变到类似弗里德赖希共济失调的表型。在排除已知的导致SCA和遗传性感觉神经病变的基因/基因座后，我们在全基因组筛查中检测到与2号染色体p臂标记的连锁关系。在测试了另外16个标记后，我们将这个新基因座命名为SCA25。在D2S2378和D2S2734处分别获得了最大两点对数优势分数3.15和3.10。单倍型分析确定了D2S2174和D2S2736之间15Mb的关键12.6cM区域。在其他四个家系中未发现与该基因座的连锁关系。这个区间包含几个可能导致该疾病的基因。其中一个基因CRIPT编码一种突触后蛋白，但通过直接测序未发现突变，排除了其与该疾病的相关性。CAG重复序列扩增常与SCA发病机制有关，但分别使用1C2抗体和重复序列扩增检测方法在蛋白质或DNA水平均未发现病理性扩增。导致SCA25的基因仍有待确定。
