Mutation Analysis of the CACNA1A Calcium Channel Subunit Gene in 27 Patients With Sporadic Hemiplegic Migraine

Terwindt, Gisela M.; Kors, Esther E.; Haan, Joost; Vermeulen, F; Maagdenberg, Arn van den; Frants, Rune R.; Ferrari, Michel D.

doi:10.1001/archneur.59.6.1016

Cited by 79 publications

(65 citation statements)

References 14 publications

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“…Sporadic patients with HM, more common in clinical practice, also present problems, since mutations in the known FHM genes are only rarely encountered in this population [45]. …”

Section: Mendelian Migraines? the Genetics Of Fhm And Their Putative mentioning

confidence: 99%

The primary headaches: genetics, epigenetics and a behavioural genetic model

Montagna

2008

J Headache Pain

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The primary headaches, migraine with (MA) and without aura (MO) and cluster headache, all carry a substantial genetic liability. Familial hemiplegic migraine (FHM), an autosomal dominant mendelian disorder classified as a subtype of MA, is due to mutations in genes encoding neural channel subunits. MA/MO are considered multifactorial genetic disorders, and FHM has been proposed as a model for migraine aetiology. However, a review of the genetic studies suggests that the FHM genes are not involved in the typical migraines and that FHM should be considered as a syndromic migraine rather than a subtype of MA. Adopting the concept of syndromic migraine could be useful in understanding migraine pathogenesis. We hypothesise that epigenetic mechanisms play an important role in headache pathogenesis. A behavioural model is proposed, whereby the primary headaches are construed as behaviours, not symptoms, evolutionarily conserved for their adaptive value and engendered out of a genetic repertoire by a network of pattern generators present in the brain and signalling homeostatic imbalance. This behavioural model could be incorporated into migraine genetic research.

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“…Sporadic patients with HM, more common in clinical practice, also present problems, since mutations in the known FHM genes are only rarely encountered in this population [45]. …”

Section: Mendelian Migraines? the Genetics Of Fhm And Their Putative mentioning

confidence: 99%

The primary headaches: genetics, epigenetics and a behavioural genetic model

Montagna

2008

J Headache Pain

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“…Apart from the absence of an affected close relative, the diagnostic criteria and attacks are identical to those in FHM (23). Most screens of FHM genes in SHM patients revealed mutations, predominantly in ATP1A2, in only a small proportion of patients (24)(25)(26)(27). Riant and colleagues (28) studied a group of 25 SHM patients with an age of onset before 16 years, of whom 18 patients had additional symptoms such as epilepsy, learning difficulties, cerebellar ataxia, and/or coma.…”

Section: Pearls In Genetics Gene Identification By Classical Linkage mentioning

confidence: 99%

Pearls and pitfalls in genetic studies of migraine

et al. 2013

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Purpose of review: Migraine is a prevalent neurovascular brain disorder with a strong genetic component, and different methodological approaches have been implemented to identify the genes involved. This review focuses on pearls and pitfalls of these approaches and genetic findings in migraine. Summary: Common forms of migraine (i.e. migraine with and without aura) are thought to have a polygenic make-up, whereas rare familial hemiplegic migraine (FHM) presents with a monogenic pattern of inheritance. Until a few years ago only studies in FHM yielded causal genes, which were identified by a classical linkage analysis approach. Functional analyses of FHM gene mutations in cellular and transgenic animal models suggest abnormal glutamatergic neurotransmission as a possible key disease mechanism. Recently, a number of genes were discovered for the common forms of migraine using a genome-wide association (GWA) approach, which sheds first light on the pathophysiological mechanisms involved. Conclusions: Novel technological strategies such as next-generation sequencing, which can be implemented in future genetic migraine research, may aid the identification of novel FHM genes and promote the search for the missing heritability of common migraine.

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“…To date 17 different mutations have been identified in the CACNA1A gene worldwide causing FHM1 [Ophoff et al, 1996;Battistini et al, 1999;Carrera et al, 1999;Ducros et al, 1999;Friend et al, 1999;Gardner et al, 1999;Vahedi et al, 2000;Ducros et al, 2001;Kors et al, 2001;Takahashi et al, 2002;Terwindt et al, 2002;Wada et al, 2002;Alonso et al, 2003;Kors et al, 2003;Alonso et al, 2004;Beauvais et al, 2004;Jen et al, 2004a;Kors et al, 2004]. In 10-20% of FHM families, the cause is a variety of missense mutations in exons of the ATP1A2 gene on chromosome 1q23 encoding the A1A2 subunit of a neuronal P-type Na þ / K þ -ATPase pump (FHM2; MIM 602481).…”

Section: Introductionmentioning

confidence: 99%

The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura

Kirchmann

Thomsen

Olesen

2006

American J of Med Genetics Pt B

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Epidemiological studies indicate that migraine with typical aura (MA) has a major genetic component but the genes for MA have not been identified. However, the autosomal dominantly inherited familial hemiplegic migraine (FHM) is often caused by mutations in the CACNA1A or ATP1A2 genes. The aim of the study was to investigate if the CACNA1A or ATP1A2 genes are involved in MA with an apparently autosomal dominant mode of inheritance. From a clinic population diagnosed by a trained physician we recruited 34 extended families (comprising 174 MA patients) with an apparently autosomal dominant mode of inheritance of MA. We performed a linkage analysis of 161 of 174 MA patients and 79 unaffected relatives using a framework marker set of 44 markers for chromosome 1 and 22 markers for chromosome 19. Linkage analysis was made with a non-parametric or autosomal dominant parametric model, either allowing for heterogeneity or not, using an affected only analysis. We identified no linkage to CACNA1A and ATP1A2 loci on chromosome 19 or 1, respectively. Additionally, at least two patients from each family and 92 healthy, unrelated controls were selected for a sequence analysis. We sequenced the 48 exons of CACNA1A and the 23 exons of ATP1A2, including promoter and flanking intron sequences. No polymorphism was identified in the CACNA1A or ATP1A2 genes with a strong correlation to MA. Our study shows that the CACNA1A or ATP1A2 genes are probably not involved in MA. To identify the genes involved in the common forms of migraine, future genetic studies should focus on MA and migraine without aura (MO) and not FHM.

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Mutation Analysis of the CACNA1A Calcium Channel Subunit Gene in 27 Patients With Sporadic Hemiplegic Migraine

Cited by 79 publications

References 14 publications

The primary headaches: genetics, epigenetics and a behavioural genetic model

The primary headaches: genetics, epigenetics and a behavioural genetic model

Pearls and pitfalls in genetic studies of migraine

The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura

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