Familial Hemiplegic Migraine and Episodic Ataxia Type-2 Are Caused by Mutations in the Ca2+ Channel Gene CACNL1A4
TL;DR: A brain-specific P/Q-type Ca2+ channel alpha1-subunit gene, CACNL1A4, covering 300 kb with 47 exons is characterized, revealing polymorphic variations, including a (CA)n-repeat (D19S1150), a (CAG) n-repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2.
About: This article is published in Cell.The article was published on 1996-11-01 and is currently open access. It has received 2264 citations till now. The article focuses on the topics: Familial hemiplegic migraine & Spinocerebellar ataxia type 6.
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TL;DR: The molecular relationships and physiological functions of these calcium channel proteins are presented and comprehensive information on their molecular, genetic, physiological, and pharmacological properties is provided.
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TL;DR: It is concluded that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
Abstract: A polymorphic CAG repeat was identified in the human α1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21‐27) compared to the number of repeats (4‐16) in 475 non‐ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human α1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
1,558 citations
TL;DR: Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation, which likely induces intracellular Ca( 2+) overload in multiple cell types.
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Cites background from "Familial Hemiplegic Migraine and Ep..."
...…hyperthermia affect skeletal muscle Boston, Massachusetts 02118 (Monnier et al., 1997; Ptacek et al., 1994), episodic ataxia affects the cerebellum (Ophoff et al., 1996), familial hemiplegic migraine affects vascular smooth muscle (Ophoff Summary et al., 1996), and stationary night blindness…...
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References
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TL;DR: A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described, providing a pure preparation of undegraded RNA in high yield and can be completed within 4 h.
65,881 citations
"Familial Hemiplegic Migraine and Ep..." refers methods in this paper
...Total RNA was isolated as previously described (Chomczynski and Sacchi, 1987)....
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TL;DR: In this article, the authors used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect, which is expanded and unstable on HD chromosomes.
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TL;DR: There is a direct correlation between the size of the (CAG)n repeat expansion and the age–of–onset of SCA1, with larger alleles occurring in juvenile cases.
Abstract: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. There is a direct correlation between the size of the (CAG)n repeat expansion and the age-of-onset of SCA1, with larger alleles occurring in juvenile cases. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.
1,586 citations