Blair Marcia A, Ma Shaochun, Hedera Peter
Department of Neurology, Vanderbilt University, Nashville, TN 37232-8552, USA.
Neurogenetics. 2006 Mar;7(1):47-50. doi: 10.1007/s10048-005-0027-8. Epub 2006 Feb 18.
Autosomal dominant hereditary spastic paraplegia (AD HSP) linked to chromosome 12q (SPG10) is caused by mutations in the neuronal kinesin heavy-chain KIF5A gene. This is a rare cause of AD HSP, and only two disease-causing mutations have been reported thus far. In both instances, affected individuals harboring mutations in the KIF5A gene displayed symptom onset at a very early age. Here we present the results of clinical and genetic analyses of a large kindred with uncomplicated AD HSP. We were able to establish a definitive linkage to the SPG10 locus, and sequencing of the KIF5A gene revealed a heterozygous missense mutation 1,035 A>G in exon 10, resulting in tyrosine-to-cysteine substitution. This mutation is located in a highly conserved kinesin motor domain of the neuronal kinesin heavy-chain protein, but in contrast to two previously reported missense mutations, the age of symptom onset in our family was much later, with an average age of 36.1+/-4 years. Our results demonstrate that mutations in the KIF5A gene can also be associated with an adult age of onset of AD HSP.
与12号染色体相关的常染色体显性遗传性痉挛性截瘫（AD HSP，SPG10）是由神经元驱动蛋白重链KIF5A基因突变引起的。这是AD HSP的一种罕见病因，迄今为止仅报道了两种致病突变。在这两个病例中，携带KIF5A基因突变的患者在非常年幼时就出现了症状。在此，我们展示了一个患有单纯性AD HSP的大家族的临床和基因分析结果。我们能够确定与SPG10位点的明确连锁关系，并且对KIF5A基因进行测序后发现外显子10中有一个杂合错义突变1035 A>G，导致酪氨酸被半胱氨酸取代。该突变位于神经元驱动蛋白重链蛋白高度保守的驱动蛋白运动结构域中，但与之前报道的两个错义突变不同的是，我们家族中症状出现的年龄要晚得多，平均年龄为36.1±4岁。我们的结果表明，KIF5A基因突变也可能与AD HSP的成人发病年龄相关。
