Bürk Katrin, Kaiser Frank J, Tennstedt Stephanie, Schöls Ludger, Kreuz Friedmar R, Wieland Thomas, Strom Tim M, Büttner Thomas, Hollstein Ronja, Braunholz Diana, Plaschke Jens, Gillessen-Kaesbach Gabriele, Zühlke Christine
Department of Neurology, Philipps University of Marburg, Germany.
Institute of Human Genetics, University of Lübeck, Germany.
Eur J Med Genet. 2014 Apr;57(5):207-11. doi: 10.1016/j.ejmg.2014.01.005. Epub 2014 Jan 29.
Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function. The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations.
脊髓小脑共济失调6型（SCA6）、发作性共济失调2型（EA2）和家族性偏瘫性偏头痛1型（FHM1）是由编码电压门控钙通道P/Q亚基的基因CACNA1A引起的等位基因疾病。虽然SCA6与影响蛋白质C末端部分的重复扩增有关，但EA2和FHM的表型通常与导致通道特性受损的无义突变和错义突变有关。在三个患有显性小脑共济失调的无关家族中，症状与进化上高度保守的氨基酸的CACNA1A错义突变（p.E668K、p.R583Q和p.D302N交换）共分离。为了评估致病作用，进行了计算机模拟和蛋白质建模分析，结果表明同源结构域2内的新突变p.E668K会导致结构改变，从而影响CACNA1A蛋白功能。该表型的特征是共济失调进展非常缓慢，而共济失调发作或偏头痛并不常见。这些发现扩大了CACNA1A突变的表型谱。
