A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia

被引:91
作者
Jen, J
Yue, Q
Nelson, SF
Yu, H
Litt, M
Nutt, J
Baloh, RW
机构
[1] Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Sch Med, Dept Pediat & Biol Chem, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Sch Med, Dept Surg, Los Angeles, CA 90095 USA
[4] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
[5] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA
关键词
D O I
10.1212/WNL.53.1.34
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Objective: 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. Background: Mutations in the CACNAlA 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, Methods: The authors used single-strand conformation polymorphism (SSCP) analysis to screen for point mutations, and direct sequencing to identify mutations in CACNAlA. 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. Results: 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 CACNAlA, predicting an early stop code at codon 1547. Two asymptomatic mutation carriers demonstrated the incomplete penetrance of this mutation. Conclusions: A nonsense mutation in CACNAlA causes episodic ataxia and complaint of weakness, and may be associated with hemiplegia.
引用
收藏
页码:34 / 37
页数:4
相关论文
共 27 条
[1]   Familial episodic ataxia: Clinical heterogeneity in four families linked to chromosome 19p [J].
Baloh, RW ;
Yue, Q ;
Furman, JM ;
Nelson, SF .
ANNALS OF NEUROLOGY, 1997, 41 (01) :8-16
[2]   IDENTIFICATION OF 2 NEW KCNA1 MUTATIONS IN EPISODIC ATAXIA MYOKYMIA FAMILIES [J].
BROWNE, DL ;
BRUNT, ERP ;
GRIGGS, RC ;
NUTT, JG ;
GANCHER, ST ;
SMITH, EA ;
LITT, M .
HUMAN MOLECULAR GENETICS, 1995, 4 (09) :1671-1672
[3]   EPISODIC ATAXIA MYOKYMIA SYNDROME IS ASSOCIATED WITH POINT MUTATIONS IN THE HUMAN POTASSIUM CHANNEL GENE, KCNA1 [J].
BROWNE, DL ;
GANCHER, ST ;
NUTT, JG ;
BRUNT, ERP ;
SMITH, EA ;
KRAMER, P ;
LITT, M .
NATURE GENETICS, 1994, 8 (02) :136-140
[4]   Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse [J].
Burgess, DL ;
Jones, JM ;
Meisler, MH ;
Noebels, JL .
CELL, 1997, 88 (03) :385-392
[5]   STRUCTURE AND FUNCTION OF VOLTAGE-GATED ION CHANNELS [J].
CATTERALL, WA .
ANNUAL REVIEW OF BIOCHEMISTRY, 1995, 64 :493-531
[6]   Episodic ataxia and myokymia syndrome: A new mutation of potassium channel gene Kv1.1 [J].
Comu, S ;
Giuliani, M ;
Narayanan, V .
ANNALS OF NEUROLOGY, 1996, 40 (04) :684-687
[7]  
GANCHER ST, 1997, ANN NEUROL, V41, P8
[8]   Spinocerebellar ataxia type 6 - Frequency of the mutation and genotype-phenotype correlations [J].
Geschwind, DH ;
Perlman, S ;
Figueroa, KP ;
Karrim, J ;
Baloh, RW ;
Pulst, SM .
NEUROLOGY, 1997, 49 (05) :1247-1251
[9]   HEREDITARY PAROXYSMAL ATAXIA - RESPONSE TO ACETAZOLAMIDE [J].
GRIGGS, RC ;
MOXLEY, RT ;
LAFRANCE, RA ;
MCQUILLEN, J .
NEUROLOGY, 1978, 28 (12) :1259-1264
[10]   EPISODIC ATAXIAS AS CHANNELOPATHIES [J].
GRIGGS, RC ;
NUTT, JG .
ANNALS OF NEUROLOGY, 1995, 37 (03) :285-287