Kapoor Ashish, Satishchandra Parthasarathy, Ratnapriya Rinki, Reddy Ramesh, Kadandale Jayaram, Shankar Susarla K, Anand Anuranjan
Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
Ann Neurol. 2008 Aug;64(2):158-67. doi: 10.1002/ana.21428.
To identify the disease locus in a three-generation south Indian family having several of its members affected with idiopathic epilepsy.
Genome-wide parametric linkage analysis was performed with 382 autosomal markers. Mutational analysis of the positional candidate genes in linked interval was performed by direct sequencing of genomic DNA from the proband in the family. Expression analysis in human adult brain was performed by Western blotting.
A novel epilepsy genetic locus on chromosome 3q13.3-q21 was identified by linkage analysis. This locus comprises about 12 megabases of the genomic interval, with its proximal and distal genetic boundaries defined by microsatellite markers, D3S3675 and D3S1551, respectively. In this interval, we found a novel, patient-specific, missense variant, Arg898Gln, at the extracellular calcium sensing receptor (CASR), a gene belonging to the G-protein-coupled receptor family. CASR expression was detected in the temporal lobe, frontal lobe, parietal lobe, cerebellum, and hippocampus. Four additional, potentially pathogenic, missense CASR variants, Glu354Ala, Ile686Val, Ala988Val, and Ala988Gly, were observed in five individuals affected with idiopathic generalized epilepsy.
A novel idiopathic epilepsy locus has been mapped on chromosome 3q13.3-q21, as evident by presence of significant genetic linkage. Identification of novel, rare missense CASR variants at evolutionary-conserved residues in epilepsy patients and CASR expression in various subregions of human brain raises an interesting possibility of involvement of CASR in pathophysiology of epileptic disorders.
在一个有多名成员患特发性癫痫的南印度三代家系中确定疾病基因座。
使用382个常染色体标记进行全基因组参数连锁分析。通过对家系中先证者的基因组DNA进行直接测序,对连锁区间内的定位候选基因进行突变分析。通过蛋白质免疫印迹法在人类成脑中进行表达分析。
通过连锁分析在3号染色体q13.3-q21区域确定了一个新的癫痫基因座。该基因座包含约12兆碱基的基因组区间,其近端和远端遗传边界分别由微卫星标记D3S3675和D3S1551确定。在这个区间内,我们在细胞外钙敏感受体(CASR)上发现了一个新的、患者特异性的错义变异体Arg898Gln,CASR是一个属于G蛋白偶联受体家族的基因。在颞叶、额叶、顶叶、小脑和海马体中检测到了CASR的表达。在另外5名患特发性全身性癫痫的个体中观察到4个额外的、可能致病的错义CASR变异体Glu354Ala、Ile686Val、Ala988Val和Ala988Gly。
通过显著的遗传连锁,在3号染色体q13.3-q21区域定位了一个新的特发性癫痫基因座。在癫痫患者进化保守残基处发现新的罕见错义CASR变异体以及在人脑各个亚区域检测到CASR表达,这提示了CASR参与癫痫疾病病理生理过程的有趣可能性。