Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura

May, Arne; Ophoff, Roel A.; Terwindt, Gisela M.; Urban, Christine; Eijk, Ronald van; Haan, Joost; Diener, H.-C.; Lindhout, Dick; Frants, Rune R.; Sandkuijl, Lodewijk A.; Ferrari, Michel D.

doi:10.1007/bf00197420

Cited by 157 publications

(92 citation statements)

References 17 publications

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“…When combining migraine with and without aura, λ s was 1.25. When the results obtained in the study including Dutch families and those obtained in our previous study, mainly including German families, 41 were combined with maximum multipoint lod score raised to 2.27 (P = 0.001 approximately). These two studies provide independent evidence of the involvement of the region on chromosome 19q13 containing the P/Q type calcium channel α 1A subunit gene in the etiology of migraine; the contribution to migraine with aura, however, seems stronger.…”

Section: Involvement Of the P/q Type Calcium Channel Gene On Chromosomentioning

confidence: 64%

“…41 However, the results were inconclusive as to the magnitude of the involvement and the relative importance of migraine with aura and migraine without aura. A second affected sib pair analysis was performed in an independent additional sample of 36 extended Dutch families, with migraine with aura and migraine without aura.…”

Section: Involvement Of the P/q Type Calcium Channel Gene On Chromosomentioning

confidence: 99%

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Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Terwindt

Ophoff²,

Haan

et al. 1998

Eur J Hum Genet

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Clinical and genetic heterogeneity as well as influence of environmental factors have hampered identification of the genetic factors which are involved in episodic diseases such as migraine, episodic ataxia and epilepsy. The study of rare, but clearly genetically determined subtypes, may help to unravel the pathogenesis of the more common forms. Recently, different types of mutation in the brain-specific P/Q type calcium channel α 1A subunit gene (CACNA1A) on chromosome 19p13 were shown to be involved in three human disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), and chronic spinocerebellar ataxia type 6 (SCA6). In addition, evidence is accumulating that the same gene is also involved in the common forms of migraine with and without aura. In the tottering and leaner mouse, which are characterised by epilepsy and ataxia, similar mutations were identified in the mouse homologue of the calcium channel α 1A subunit gene. These findings add to the growing list of episodic (and now also chronic) neurological disorders, which are caused by inherited abnormalities of voltage-dependent ion channels. The findings in migraine illustrate that rare, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more complex, forms.

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Section: Involvement Of the P/q Type Calcium Channel Gene On Chromosomentioning

confidence: 64%

Section: Involvement Of the P/q Type Calcium Channel Gene On Chromosomentioning

confidence: 99%

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Terwindt

Ophoff²,

Haan

et al. 1998

Eur J Hum Genet

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“…The ATP1A2 gene on chromosome 1q23 (FHM2) [De Fusco et al, 2003;Vanmolkot et al, 2003], the SCN1A gene on chromosome 2q24 , and the CACNA1A gene on 19p13 (FHM1) [Joutel et al, 1993;Ophoff et al, 1996] have been implicated in this autosomal dominantly inherited disorder. Evidence is accumulating that the chromosome 1 and 19 loci may also be involved in the common migraines, although more research is required to confirm these findings [Hovatta et al, 1994;May et al, 1995;Ophoff et al, 1997;Nyholt et al, 1998Nyholt et al, , 2005Jones et al, 2001;Terwindt et al, 2001;Todt et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

A genome‐wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

Ligthart

Nyholt

Hottenga

et al. 2008

American J of Med Genetics Pt B

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Latent class analysis was performed on migraine symptom data collected in a Dutch population sample (N ¼ 12,210, 59% female) in order to obtain empirical groupings of individuals suffering from symptoms of migraine headache. Based on these heritable groupings (h 2 ¼ 0.49, 95% CI: 0.41-0.57) individuals were classified as affected (migrainous headache) or unaffected. Genomewide linkage analysis was performed using genotype data from 105 families with at least 2 affected siblings. In addition to this primary phenotype, linkage analyses were performed for the individual migraine symptoms. Significance levels, corrected for the analysis of multiple traits, were determined empirically via a novel simulation approach. Suggestive linkage for migrainous headache was found on chromosomes 1 (LOD ¼ 1.63; pointwise P ¼ 0.0031), 13 (LOD ¼ 1.63; P ¼ 0.0031), and 20 (LOD ¼ 1.85; P ¼ 0.0018). Interestingly, the chromosome 1 peak was located close to the ATP1A2 gene, associated with familial hemiplegic migraine type 2 (FHM2). Individual symptom analysis produced a LOD score of 1.97 (P ¼ 0.0013) on chromosome 5 (photo/ phonophobia), a LOD score of 2.13 (P ¼ 0.0009) on chromosome 10 (moderate/severe pain intensity) and a near significant LOD score of 3.31 (P ¼ 0.00005) on chromosome 13 (pulsating headache). These peaks were all located near regions previously reported in migraine linkage studies. Our results provide important replication and support for the presence of migraine susceptibility genes within these regions, and further support the utility of an LCA-based phenotyping approach and analysis of individual symptoms in migraine genetic research. Additionally, our novel ''2-step'' analysis and simulation approach provides a powerful means to investigate linkage to individual trait components.

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“…those with and without aura, henceforth called "typical" migraines. Some evidence in favor of this idea was found by May et al [18] and Nyholt et al [19], but several other studies have instead given negative results. Sequencing of the CACNA1A gene in selected families has proven negative, and as yet no family has been reported with non-hemiplegic migraine and a mutation of CACNA1A.…”

Section: Familial Hemiplegic Migrainementioning

confidence: 94%

The genetics of migraine

Montagna

2001

J Headache Pain

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Migraine is currently considered to be a multifactorial disease in that it is modified by environmental and genetic factors and has a polygenic determination. Familial hemiplegic migraine (FHM), a subtype of migraine with aura conforming to simple mendelian transmission, has been shown to result from mutations in the CACNA1A gene, a neural calcium channel gene. FHM is allelic with episodic ataxia type 2 and spinocerebellar ataxia type 6. FHM is genetically heterogeneous, with at least another linkage locus on chromosome 1. Association and linkage studies have also been performed in migraine with and without aura, the so–called typical migraines, without however definite results up to now.

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Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura

Cited by 157 publications

References 17 publications

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies

A genome‐wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

The genetics of migraine

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