The interplay of two single nucleotide polymorphisms in the CACNA1A gene may contribute to migraine susceptibility

Migraine is a common disorder with a significant genetic component. Mutations in the CACNA1A gene are found in hemiplegic migraine (HM). Basilar-type (BM), another subtype of migraine with aura, differs from HM only by the absence of motor deficits. BM and HM may thus share common genetic features. In the present study, two single nucleotide polymorphisms (SNPs) of the CACNA1A gene were characterized in a population of migraine patients and healthy controls. The polymorphisms, E918D, predicting a glutamic acid-to-aspartic acid substitution at codon 918 and E993V, predicting a glutamic acid-to-valine substitution at codon 993, were frequently detected among patients and controls. Seven BM, 10 SHM, 5 FHM, 57 migraine with typical aura, 32 migraine without aura patients and 107 healthy controls were screened. The E918D and E993V SNPs were found in 30/117 (25.6%) and 32/117 (27.3%) migraine patients, respectively. The prevalence of these SNPs taken separately was not significantly different from that of control subjects (n = 28/107, 26.2% for E918D; n = 29/107 for E993V, 27.1%) neither for the total migraine population nor for the various migraine subtypes. By contrast, coexistence of both SNPs was more frequent in migraineurs (25/117, 21%) than in healthy controls (12/107, 11%; p = 0.048), a difference that was significant for every migraine subtype. This result suggests that the interplay of minor genetic variants such as single nucleotide polymorphisms may influence the P/Q-type calcium channel function in several subtypes of migraine.     

Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility.

Typical migraine is a complex neurological disorder comprised of two main subtypes: migraine with (MA) and without aura (MO). The disease etiology is still unclear, but family studies provide strong evidence that defective genes play an important role. Familial hemiplegic migraine (FHM) is a very rare and severe subtype of MA. It has been proposed that FHM and MA may have a similar genetic etiology. Therefore, genetic studies on FHM provide a useful model for investigating the more prevalent types of typical migraine. FHM in some families has been shown to be caused by mutations in a brain-specific P/Q-type calcium channel alpha1 subunit gene (CACNA1A) on chromosome 19p13. There has also been a report of a CACNA1A mutation being associated with MA in a patient from a family with predominant FHM. We have previously demonstrated suggestive linkage of typical migraine in a large Australian family to the FHM region on chromosome 19p13. These findings suggest that CACNA1A may also be implicated in the etiology of typical migraine in this pedigree. To investigate this possibility, we sequenced two patients carrying the critical susceptibility haplotype surrounding CACNA1A. No disease-causing mutations or polymorphisms were revealed in any of the 47 exons screened. To determine whether the CACNA1A gene was implicated in typical migraine susceptibility in the general Caucasian population, we also analyzed 82 independent pedigrees and a large case control group. We did not detect any linkage or association in these groups and conclude that if CACNA1A plays a role in typical migraine, it does not confer a major effect on the disease.     

CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine

Of the 18 missense mutations in the CACNA1A gene, which are associated with familial hemiplegic migraine type 1 (FHM1), only mutations S218L, R583Q and T666M were identified in more than two independent families. Including the four novel families presented here, of which two represent de novo cases, the R1347Q mutation has now been identified in six families. A genotype-phenotype comparison of R1347Q mutation carriers revealed a wide clinical spectrum ranging from (trauma triggered) hemiplegic migraine with and without ataxia, loss of consciousness and epilepsy. R1347Q is the third most frequent mutation in hemiplegic migraine patients and should therefore be screened with priority for confirmation of clinical diagnosis. This study clearly demonstrates that the availability of multiple families better reflects the full clinical spectrum associated with FHM1 mutations.     

Multilocus analysis reveals three candidate genes for Chinese migraine susceptibility

Several genome‐wide association studies (GWASs) in Caucasian populations have identified 12 loci that are significantly associated with migraine. More evidence suggests that serotonin receptors are also involved in migraine pathophysiology. In the present study, a case–control study was conducted in a cohort of 581 migraine cases and 533 ethnically matched controls among a Chinese population. Eighteen polymorphisms from serotonin receptors and GWASs were selected, and genotyping was performed using a Sequenom MALDI‐TOF mass spectrometry iPLEX platform. The genotypic and allelic distributions of MEF2D rs2274316 and ASTN2 rs6478241 were significantly different between migraine patients and controls. Univariate and multivariate analysis revealed significant associations of polymorphisms in the MEF2D and ASTN2 genes with migraine susceptibility. MEF2D, PRDM16 and ASTN2 were also found to be associated with migraine without aura (MO) and migraine with family history. And, MEF2D and ASTN2 also served as genetic risk factors for the migraine without family history. The generalized multifactor dimensionality reduction analysis identified that MEF2D and HTR2E constituted the two‐factor interaction model. Our study suggests that the MEF2D, PRDM16 and ASTN2 genes from GWAS are associated with migraine susceptibility, especially MO, among Chinese patients. It appears that there is no association with serotonin receptor related genes.     

CACNA1S基因突变致低钾周期性麻痹的产前基因诊断

目的对CACNA1S基因R1239H突变导致的低钾周期性麻痹（HoKPP1型）家系中的1例中期妊娠者进行产前基因诊断,从而预防HoKPP患儿出生。方法患者于16孕周在B超下进行羊膜囊穿刺,抽取羊水10 mL,提取羊水细胞基因组DNA。选择3个多态性STR位点,D13S317、D8S1179和D16S539,排除母体细胞的污染。在此基础上对CAC-NA1S基因外显子30进行扩增,PCR产物进行正、反向测序。结果 STR多态性位点分析,证明无母体细胞污染,胎儿CACNA1S基因30外显子测序结果显示,胎儿带有和母亲同样的CACNA1S基因突变R1239H。结论对于有HoKPP风险的胎儿进行产前基因诊断非常重要,可以明确胎儿基因型,预防患儿出生。     

Familial migraine with vertigo: No mutations found in CACNA1A

We searched for mutations in the voltage-gated calcium channel gene, CACNA1A, in nine propositi of families with migraine headaches and episodic vertigo inherited in an autosomal dominant pattern. All 47 exons and flanking introns in CACNA1A were subjected to single-strand conformation polymorphism analysis of polymerase chain reaction-amplified genomic DNA. Exons with aberrantly migrating fragments were sequenced using standard techniques. We also determined the CAG repeat length at the 3′ end of CACNA1A. Several polymorphisms were found but no mutations identified in any of the 47 exons of the 9 patients. No index-case had a CAG repeat length greater than 13 (normal <17). Mutations in CACNA1A are not common in families with migraine headaches and episodic vertigo. Other ion channel genes expressed in the brain and inner ear remain candidate genes. Am. J. Med. Genet. 79:148–151, 1998. © 1998 Wiley-Liss, Inc.     

CACNA1H variants are not a cause of monogenic epilepsy

CACNA1H genetic variants were originally reported in a childhood absence epilepsy cohort. Subsequently, genetic testing for CACNA1H became available and is currently offered by commercial laboratories. However, the current status of CACNA1H as a monogenic cause of epilepsy is controversial, highlighted by ClinGen's recent reclassification of CACNA1H as disputed. We analyzed published CACNA1H variants and those reported in ClinVar and found none would be classified as pathogenic or likely pathogenic per the American College of Medical Genetics classification criteria. Moreover, Cacna1h did not modify survival in a Dravet Syndrome mouse model. We observed a mild increase in susceptibility to hyperthermia‐induced seizures in mice with reduced Cacna1h expression. Overall, we conclude that there is limited evidence that CACNA1H is a monogenic cause of epilepsy in humans and that this gene should be removed from commercial genetic testing panels to reduce the burden of variants of uncertain significance for healthcare providers, families and patients with epilepsy.     

Investigation of CD69 as a new candidate gene for rheumatoid arthritis

The aim of this study was to investigate the CD69 gene as a new functional candidate gene for rheumatoid arthritis (RA) genetic predisposition. A case–control association study including 933 RA patients and 800 healthy individuals was conducted. Five haplotype-tagging single nucleotide polymorphisms (SNPs) (rs929615, rs3176806, rs4763299, rs11052877, and rs3176789) covering the CD69 gene coding, 5' and 3' untranslated regions were selected as CD69 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. No statistically significant differences were observed in the single marker association study with regard to either genotypic or allelic frequencies when considering the rs929615, rs3176806, rs4763299, rs11052877, and rs3176789 CD69 SNPs independently. According to these findings, no statistically significant skewing was observed between the RA patients and the controls in the distribution of CD69 haplotypes. In summary, our results do not support a major role for the CD69 gene polymorphisms in RA genetic predisposition in our population.     

The novel p.L1649Q mutation in the SCN1A epilepsy gene is associated with familial hemiplegic migraine: genetic and functional studies

Familial hemiplegic migraine (FHM) is a severe subtype of migraine with hemiparesis during attacks. We scanned 10 families with FHM without mutations in the CACNA1A (FHM1) and ATP1A2 (FHM2) genes. We identified the novel p.L1649Q mutation (c.4946T>A) in Na_v1.1 sodium channel gene SCN1A (FHM3) in a North American kindred with FHM without associated ataxia or epilepsy. Functional analysis of the mutation, introduced in the highly homologous human SCN5A, revealed markedly slowed inactivation and a two-fold faster recovery from fast inactivation predicting enhanced neuronal excitation. Our findings establish the role of neuronal Na_v1.1 sodium channels in FHM and reinforce the involvement of ion channel dysfunction in the pathogenesis of this episodic brain disorder. © 2007 Wiley-Liss, Inc.     

子宫内膜异位症与细胞色素P450 1A1基因A4889G突变的相关性

目的探讨细胞色素P450 1A1(cytochrome P450 1A1,CYP1A1)基因A4889G突变与子宫内膜异位症(endometriosis,EM)的遗传易感性的关系.方法采用等位基因特异性聚合酶链反应的方法,研究了76例EM患者和80名正常对照CYP1A1基因A4889G位点碱基突变.两组均为广东籍汉族妇女.结果 CYP1A1基因A4889G位点等位基因A、G在EM组和对照组分布的差异有显著性(χ2=7.498,P<0.01),其中等位基因G使患EM的相对危险度提高了1.957倍.CYP1A1基因A4889G位点各基因型分布在两组间差异有显著性(χ2=6.915,P<0.05),GG基因型与AA基因型相比患EM的危险度高3.437倍(χ2=5.430,P<0.05).结论 CYP1A1基因A4889G突变等位基因与EM有一定的关联,突变基因型增加了EM的发病风险.     

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

Panic disorder (PD) is a mental disorder with recurrent panic attacks that occur spontaneously and are not associated to any particular object or situation. There is no consensus on what causes PD. However, it is recognized that PD is influenced by environmental factors, as well as genetic factors. Despite a significant hereditary component, genetic studies have only been modestly successful in identifying genes of importance for the development of PD. In this study, we conducted a genome-wide scan using microsatellite markers and PD patients and control individuals from the isolated population of the Faroe Islands. Subsequently, we conducted a fine mapping, which revealed the amiloride-sensitive cation channel 1 (ACCN1) located on chromosome 17q11.2-q12 as a potential candidate gene for PD. The further analyses of the ACCN1 gene using single-nucleotide polymorphisms (SNPs) revealed significant association with PD in an extended Faroese case-control sample. However, analyses of a larger independent Danish case-control sample yielded no substantial significant association. This suggests that the possible risk alleles associated in the isolated population are not those involved in the development of PD in a larger outbred population.     

一个短指家系临床特征调查及其致病基因的定位

目的 通过对山东省一个A1型短指(brachydactyly type A1,BDA1)家系的临床特征及致病基因分析,确定该病的遗传类型及其发生机制.方法 经家系调查及临床检查确定疾病类型;通过致病基因微卫星多态位点进行连锁分析;采用修饰引物产生引入酶切位点的方法来区分突变基因.结果 该家系的短指症为A1型,常染色体显性遗传;发病原因为位于染色体2q35-2q36的IHH基因(indian hedgehog gene)发生了G298A(D100N)错义突变.结论 中国山东A1型短指家系的发病机理是IHH基因发生了G298A(D100N)错义突变所致.     

一个短指家系临床特征调查及其致病基因的定位

目的 通过对山东省一个A1型短指(brachydactyly type A1,BDA1)家系的临床特征及致病基因分析,确定该病的遗传类型及其发生机制.方法 经家系调查及临床检查确定疾病类型;通过致病基因微卫星多态位点进行连锁分析;采用修饰引物产生引入酶切位点的方法来区分突变基因.结果 该家系的短指症为A1型,常染色体显性遗传;发病原因为位于染色体2q35-2q36的IHH基因(indian hedgehog gene)发生了G298A(D100N)错义突变.结论 中国山东A1型短指家系的发病机理是IHH基因发生了G298A(D100N)错义突变所致.