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      Association of single nucleotide polymorphisms of CACNA1A gene in migraine

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          Abstract

          INTRODUCTION:

          Migraine is a chronic, neurovascular polygenic disease where genetic and environmental factors are involved in its etiology. Dysfunction of neuronal ion transportation can provide a model for predisposition for common forms of migraine. Mutations in genes encoding ion channels disturb the rhythmic function of exposed tissue that may also explain the episodic nature of migraine. Our aim was to study the single nucleotide polymorphisms of CACNA1A gene in migraine patients.

          MATERIALS AND METHODS:

          The subjects were the patients of migraine, in the age range of 18-80 years, diagnosed by a Neurologist, as per the diagnostic criteria of International Headache Society (IHS) Classification 2004 after excluding other causes of headache by clinical examination and relevant investigations.

          The controls were the age and sex matched healthy persons from the same population excluding the relatives of patients. Only those patients and the controls, who voluntarily participated in the study, were taken and their blood samples were taken for the study. Deoxyribonucleic acid (DNA) extraction was performed according to the manufacturer's protocol for Qiagen DNA extraction kits (Qiagen, Hilden, NRW, Germany). DNA content was quantified by spectrophotometric absorption (Nanodrop Spectrophotometer, BioLab, Scoresby, VIC, Australia). Polymerase chain reaction was performed using an iCycler Thermal Cycler (Bio.Rad, Hercules, CA, USA). The polymorphic analysis of CACNA1A gene was carried out by two methods: Restriction fragment length polymorphism and sequencing.

          RESULTS:

          The study included a total of 25 patients of migraine, diagnosed on out-patient department basis as per IHS Classification 2004 and compared with age and sex matched 25 healthy controls. Most of the patients 23 (92%) were below the age of 50 years. 20 of the patients (80%) were females and 5 (20%) were males. The polymorphic analysis of CACNA1A gene revealed the presence of only the wild form of the gene for the codon E993V in both case and control groups.

          CONCLUSION:

          In our study, we could not find any polymorphism of CACNA1A gene in the selected patients. Instead the wild type of genotype was found in both patients and controls. This negative result presented here, implies that if the CACNA1A gene is involved in typical migraine (with and without aura), its contribution is very modest and therefore difficult to discern. Nevertheless, there are other genes that could be considered potential candidates for typical migraine susceptibility for which further research is needed.

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          Most cited references19

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          The International Classification of Headache Disorders: 2nd edition.

          (2004)
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            Prevalence of headache and migraine in schoolchildren.

            To determine the prevalence rates of the various causes of severe headache in schoolchildren, with special emphasis on migraine and its impact on school attendance. Population based study in two stages, comprising an initial screening questionnaire followed by clinical interviews and examination of children with symptoms and a control group of asymptomatic children matched for age and sex. 67 primary and secondary schools in the city of Aberdeen. 2165 children, representing a random sample of 10% of schoolchildren in Aberdeen aged 5-15 years. (a) the prevalence of migraine (International Headache Society criteria) and of other types of headache; (b) the impact of migraine on school attendance. The estimated prevalence rates of migraine and tension headache were 10.6% (95% confidence interval 9.1 to 12.3) and 0.9% (0.5 to 1.5) respectively. The estimated prevalence rates for migraine without aura and migraine with aura were 7.8% (95% confidence interval 6.5 to 9.3) and 2.8% (2.0 to 3.8) respectively. In addition, 10 children (0.7%) had headaches which, though lasting less than two hours, also fulfilled the International Headache Society criteria for migraine, 14 (0.9%) had tension headaches, and 20 (1.3%) had non-specific recurrent headache. The prevalence of migraine increased with age, with male preponderance in children under 12 and female preponderance thereafter. Children with migraine lost a mean of 7.8 school days a year due to all illnesses (2.8 days (range 0-80) due to headache) as compared with a mean of 3.7 days lost by controls. Migraine is a common cause of headache in children and causes significantly reduced school attendance.
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              Familial hemiplegic migraine.

              Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming alpha(1) subunits of the neuronal voltage-gated Ca2+ channels Ca(V)2.1 and Na+ channels Na(V)1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the alpha2 subunit of the Na+, K+ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca(V)2.1 channel and, as a consequence, increased Ca(V)2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the alpha2 Na+,K+-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na(V)1.5 (and presumably Na(V)1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K+ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K+ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.
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                Author and article information

                Journal
                Indian J Hum Genet
                Indian J Hum Genet
                IJHG
                Indian Journal of Human Genetics
                Medknow Publications & Media Pvt Ltd (India )
                0971-6866
                1998-362X
                Jan-Mar 2014
                : 20
                : 1
                : 59-63
                Affiliations
                [1]Department of Neurology, SKIMS, Soura, Srinagar, Jammu and Kashmir, India
                [1 ]Department of Immunology, SKIMS, Soura, Srinagar, Jammu and Kashmir, India
                Author notes
                Address for correspondence: Dr. Irfan Yousuf Wani, Department of Neurology, SKIMS, Soura, Srinagar, Jammu and Kashmir, India. E-mail: drirfanyousuf@ 123456gmail.com
                Article
                IJHG-20-59
                10.4103/0971-6866.132757
                4065480
                24959015
                81080da3-a679-4b96-92ff-7b8183f30af0
                Copyright: © Indian Journal of Human Genetics

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Original Article

                Genetics
                cacna1a gene,migraine,polymorphism
                Genetics
                cacna1a gene, migraine, polymorphism

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