Jen J, Yue Q, Nelson S F, Yu H, Litt M, Nutt J, Baloh R W
Department of Neurology, University of California at Los Angeles School of Medicine, 90095-1769, USA.
Neurology. 1999 Jul 13;53(1):34-7. doi: 10.1212/wnl.53.1.34.
To identify the disease-causing mutation and to characterize penetrance and phenotypic variability in a large pedigree with episodic ataxia type 2 (EA-2) previously linked to chromosome 19.
Mutations in the CACNA1A gene on chromosome 19 encoding a calcium channel subunit cause EA-2, which is characterized by recurrent attacks of imbalance with interictal eye movement abnormalities.
The authors used single-strand conformation polymorphism (SSCP) analysis to screen for point mutations, and direct sequencing to identify mutations in CACNA1A. Allele-specific oligonucleotides were designed to detect the presence of the diseased allele in members of their pedigree as well as in normal control subjects.
Reassessment of members of the pedigree revealed two notable clinical features. Diffuse weakness during attacks of ataxia was a prominent complaint. Two affected individuals had had episodic hemiplegia, one with typical migraine headaches. SSCP analysis revealed aberrant bands in exon 29 in affected members but not in normal control subjects. Direct sequencing of exon 29 identified a C-to-T change at position 4914 of the coding sequence of CACNA1A, predicting an early stop code at codon 1547. Two asymptomatic mutation carriers demonstrated the incomplete penetrance of this mutation.
A nonsense mutation in CACNA1A causes episodic ataxia and complaint of weakness, and may be associated with hemiplegia.
在一个先前已与19号染色体连锁的发作性共济失调2型(EA - 2)的大型家系中鉴定致病突变,并描述其外显率和表型变异性。
19号染色体上编码钙通道亚基的CACNA1A基因突变导致EA - 2,其特征为反复发作的失衡伴发作间期眼动异常。
作者使用单链构象多态性(SSCP)分析筛选点突变,并通过直接测序鉴定CACNA1A中的突变。设计等位基因特异性寡核苷酸以检测其家系成员以及正常对照受试者中患病等位基因的存在。
对家系成员的重新评估揭示了两个显著的临床特征。共济失调发作期间的弥漫性无力是一个突出的主诉。两名受影响个体曾有发作性偏瘫,其中一人伴有典型偏头痛。SSCP分析显示受影响成员的第29外显子有异常条带,而正常对照受试者中没有。第29外显子的直接测序确定了CACNA1A编码序列第4914位的C到T变化,预测在密码子1547处出现早期终止密码。两名无症状突变携带者显示出该突变的不完全外显率。
CACNA1A中的一个无义突变导致发作性共济失调和无力主诉,并且可能与偏瘫有关。