Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
复制标题
DOI：
10.1056/nejmoa2207406
复制
发表时间：
2023-01-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
晚发性小脑共济失调（LOCAS）在很大程度上抵制分子诊断。我们对来自三个法裔加拿大家庭的六名常染色体显性LOCA患者的基因组进行了测序，并确定了一个候选的致病性重复扩增。然后，我们在两个独立的病例对照系列中测试了重复扩增与疾病之间的关联-一个是法裔加拿大人（66名患者和209名对照），另一个是德国人（228名患者和199名对照）。我们还对20名澳大利亚和31名印度索引患者的重复进行了基因分型。我们检测了两个死后小脑标本和两个诱导多能干细胞（iPSC）衍生的运动神经元细胞系的基因和蛋白质表达。在6名法裔加拿大患者中，我们发现了一个GAA重复扩增深入FGF 14的第一个内含子，编码成纤维细胞生长因子14。家系中重复扩增与疾病的共分离支持致病阈值至少为250个GAA重复（[GAA]≥250）。在法裔加拿大人系列（比值比，105.60; 95%可信区间[CI]，31.09 - 334.20; P<0.001）和德国系列（比值比，8.76; 95% CI，3.45 - 20.84; P<0.001）中，FGF 14（GAA）≥250扩增与LOCA之间存在显著相关性。法裔加拿大人、德国人、澳大利亚人和印度索引患者中分别有61%、18%、15%和10%存在重复扩增。我们总共确定了128例携带FGF 14（GAA）≥250扩增的LOCA患者。来自患者的死后小脑标本和iPSC衍生的运动神经元显示FGF 14 RNA和蛋白质的表达减少。发现FGF 14中显性遗传的深内含子GAA重复扩增与LOCA相关。（由摩纳哥基金会和其他机构资助）
The late-onset cerebellar ataxias (LOCAS) have largely resisted molecular diagnosis. We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case–control series — one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)–derived motor-neuron cell lines. In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.)