Goizet Cyril, Boukhris Amir, Mundwiller Emeline, Tallaksen Chantal, Forlani Sylvie, Toutain Annick, Carriere Nathalie, Paquis Véronique, Depienne Christel, Durr Alexandra, Stevanin Giovanni, Brice Alexis
INSERM, UMR_S679, Paris, France.
Hum Mutat. 2009 Feb;30(2):E376-85. doi: 10.1002/humu.20920.
Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. Only a few different mutations in the SPG10 gene, KIF5A, have been described in pure dominant forms of the disease. We sequenced the motor domain of KIF5A in a large panel of 205 European HSP patients with either pure or complicated forms of the disease. We identified eight different heterozygous missense mutations, seven novels, in eight different families of French origin. Residue R280 was a mutational hot spot. Interestingly, the patients in 7/8 families had a complex phenotype, with peripheral neuropathy, severe upper limb amyotrophy (Silver syndrome-like), mental impairment, parkinsonism, deafness and/or retinitis pigmentosa as variably associated features. We report the largest series of SPG10 families described so far, which extends both the mutational spectrum of the disease and its phenotype, which now includes complicated forms of HSP. SPG10 mutations were found in 10% of our complicated forms of HSP, suggesting that mutations in KIF5A represent the major cause of complicated AD-HSP in France.
遗传性痉挛性截瘫（HSP）是一组异质性神经退行性疾病，其特征为下肢进行性痉挛。在该疾病的纯显性形式中，仅描述了SPG10基因（KIF5A）中的少数几种不同突变。我们对205名患有纯合或复杂形式疾病的欧洲HSP患者进行了大规模队列研究，对KIF5A的运动结构域进行了测序。我们在8个不同的法裔家族中鉴定出8种不同的杂合错义突变，其中7种为新突变。残基R280是一个突变热点。有趣的是，8个家族中有7个家族的患者具有复杂的表型，伴有周围神经病变、严重上肢肌萎缩（类Silver综合征）、智力障碍、帕金森综合征、耳聋和/或色素性视网膜炎等不同程度的相关特征。我们报告了迄今为止描述的最大系列的SPG10家族，这扩展了该疾病的突变谱及其表型，现在包括复杂形式的HSP。在我们10%的复杂形式HSP中发现了SPG10突变，这表明KIF5A突变是法国复杂常染色体显性遗传HSP的主要原因。
