三种神经系统遗传疾病的分子和细胞遗传学研究
|
摘要
遗传性疾病是人的遗传物质在数量、结构或功能上发生改变,干扰了正常的生命活动而引起的疾病,也是一类能够通过生殖细胞传递给后代的疾病。神经系统的遗传病是所有遗传病中最为重要的一类,是神经系统疾病和医学遗传学的重要组成部分。在众多神经系统遗传病中,癫痫(epilepsy)占有重要位置,其发病率很高,Fahr病的致残率很高,智力障碍(mental retardation,MR)的发病率也很高,它们是重要的神经系统疾病。本论文对上述神经系统遗传病进行分子和细胞遗传研究,以期克隆相关致病基因,同时对克隆的致病基因进行功能研究,揭示上述疾病的发病机制,为治疗这类疾病奠定基础。
癫痫是一种常见的慢性脑部疾病,由多种病因引起的慢性脑功能障碍综合征,具有发作性、复发性和自然缓解性的特点。据估计,癫痫患者约占世界人口的0.5-1%,极大危害人类健康。根据遗传方式可将其分为四大类:单基因遗传病、多基因病遗传病、染色体畸变遗传病、线粒体遗传病。该病又呈现出高度临床表现异质性和遗传异质性。家族性基底节脑血管钙化又称Fahr病,是一种神经系统锥体外系遗传病,伴随癫痫、运动障碍和智力、意识障碍等发生,大多数家系表现为常染色体显性遗传方式,也有常染色体隐性遗传和性染色体遗传的报道,具有广泛的遗传异致性。智力障碍,也称精神发育迟缓是指18岁以前发育阶段由于遗传因素、环境因素和社会心理因素等各种原因所引起,临床表现为智力明显低下和社会适应能力缺陷为主要特征的一组疾病。许多染色体病伴随智力障碍的发生。
(1)在一个来自中国河南的常染色体显性遗传小儿癫痫家系中,通过连锁分析排除所有已知癫痫致病基因和已知位点,对该家系进行全基因组扫描工作,将该家系的致病基因定位在3号染色体长臂上位于D3S3656和D3S1232标记之间大约10.7Mb的区域(3q26.2—q26.33,所获得的两点最大LOD值是4.13)。这是一个新的癫痫致病基因位点。在定位区段内,共有24个已知基因和24个已知的EST。利用突变体检测技术,我们分析了此区域内的18个可能的候选基因,但是没有发现与疾病相关突变。由于我们定位了一个新的癫痫致病位点,该项目的进一步研究有望克隆新的癫痫致病基因。
(2)在河南收集并鉴定了一个5代共31名成员的常染色体显性Fahr病大家系,通过连锁分析排除Fahr病已知致病位点14q13.1-q23.1,对该家系进行全基因组扫描工作,将该家系的致病基因定位在8号染色体上两个标记D8S1809和D8S1833之间大约25.0Mb的区域(8p21.2-q11.23),与D8S505紧密连锁,最大两点LOD值是4.10。此位点是世界上第二个Fahr病致病遗传位点。对该区域内的一个在大脑中广泛表达的SNTG1基因进行测序分析,未发现突变。由于目前还没克隆到Fahr病的相关致病基因,所以本研究为进一步克隆到世界上第一个新Fahr病致病基因奠定了基础。
(3)对来自河南的伴随智力障碍、发育迟缓和手、面部轻微畸形患者进行染色体核型分析,发现是9p部分三体综合征。家系1内的先证者除表现出典型的9p部分三体综合征外,同时患有癫痫。经染色体G-显带分析发现家系1内的先证者核型为46,XY,-21,+der(21),t(9;21)。其父亲、伯父为46,XY,t(9;21)平衡易位核型,母亲核型正常,可知异常染色体来自父亲。所以家系1的先证者核型为46,XY,-21,+der(21),t(9;21)pat。而家系2的先证者除表现出典型的9p部分三体综合征外,并伴有皮肤湿疹症状。G显带核型为46,XY,+der(5),t(5;9),其母亲为46,XX,t(5;9)平衡易位核型,父亲核型正常,所以家系2的先证者核型为46,XY,+der(5),t(5;9)mat。进一步的临床调查发现家系1内另有癫痫患者,但G-显带分析发现他们的核型是正常的。而家系2中无其他人有智障及皮肤湿疹症状。利用荧光原位杂交分析进一步证明了核型分析结果。染色体断裂点分析表明,家系1内的9p断裂点位于D9S1846与D9S171之间,大约2.9Mb;而家系2内的9p断裂点位于D9S1870和D9S1679之间,大约2.7Mb。两个先征者的精确核型分别是:46,XY,-21,+der(21),t(9;21)(p21.3;q22.3)pat,46,XY,+der(5),t(5;9)(p15.3;p21.3)mat。虽然两个家系内的患者具有相似的9p复制区域24.4/24.7 Mb(9p21.3 to 9pter),但两个家系患者除都具有典型的9p部分三体综合征外,并伴有独特的临床症状。分析发现9p三体与智力障碍相关,9p21.3→9ter这段区域可能存在与智力发育相关的基因。
所有这些分子细胞遗传学研究为阐明神经系统遗传病的病理学,以及提供更好的遗传咨询和最终发展有效疾病治疗策略提供了有益的帮助。
Genetic disease can be transmitted to offspring by germ cells and caused by instability of genetic materials,including chromosomal aberrations and gene mutations. Genetic disease in the nervous system is not only the most important inherited disorder, but also a very important part of the neurological diseases and medical genetics. Epilepsy and mental retardation are major neurological disorders and have a high incidence.Fahr disease,another neurological disease,has a high disability rate.In this study,a molecular cytogenetic approach was used to study the inherited neurogenetic diseases in order to find the genes or mutations responsible for these diseases. Functional studies on a pathogenic gene will benefit understanding of mechanisms,and could offer a foundation to therapy of these diseases.
Epilepsy is a chronic disorder of the brain and characterized by the imbalance of neurotransmitters and the abnormal discharge of the neuron.The main characteristics are paroxysmal,recurrent and natural relief.The incidence of epilepsy is 0.5-1%. Hereditary epilepsies were divided into four groups such as single-gene disorders, polygene disorders,chromosome disease,and mitochondria disease.The disease shows wide phenotypic and genetic heterogeneity.Familial idiopathic basal ganglia calcification (IBGC,Fahr disease) is another inherited neurologic condition characterized by basal ganglia and extra-basal ganglia brain calcifications,parkinsonism,and neuropsychiatric symptoms.The major pattern of inheritance is autosomal dominant and autosomal recessive,but X-linked inheritance was also found,which demonstrates genetic and clinical heterogeneity of familial IBGC.Mental retardation is defined by significant limitations in intellectual functions and adaptive behaviors that occur before the age of 18 years.The etiology for mental retardation is highly heterogeneous,and involves many cellular pathways and processes.Both genetic defects and environmental insults,alone or in combination,are known to cause cognitive impairment in humans.Many chromosomal diseases are associated with mental retardation.
(1) A four-generation Chinese family with autosomal dominant febrile seizure and epilepsy was studied by genome-wide linkage analysis after exclusion of known loci and genes for epilepsy.Significant linkage was identified with markers on chromosome 3q26.2-26.33 with a maximum pairwise LOD score of 4.13.Fine mapping defined the new genetic locus within a 10.7 Mb region between markers D3S3656 and D3S1232.Our results identified another novel locus on chromosome 3q26.2-26.33.There are 24 candidate genes and EST in the novel locus region respectively.We analyzed 18 candidate genes in this region,but no mutation was found.A new genetic locus was obtained in our study,which provides a framework for future identification of the specific gene responsible for epilepsy.
(2) We characterized a large five-generation Chinese family with Fahr disease,in which 31 family members were used for genome-wide linkage analysis.After exclusion of the unique genetic locus located on chromosome 14q13.1-q23.1,haplotype and two-point LOD analysis had been performed to define the disease gene interval.The Fahr disease locus in the family was mapped to chromosome 8p21.2-q11.23 with the maximum two-point LOD scores of 4.10 for marker D8S505,and the gene was found to be within a 25.0 Mb interval between markers D8S1809 and D8S1833.Mutation analysis of the SNTG1 gene at the locus,which is specifically expressed in the brain,did not reveal a disease causing mutation.To date,the gene responsible for Fahr disease is not found.Our study provides a framework for identification of a first pathogenic gene for Fahr disease.
(3) Two Chinese families with metal retardation and delayed development in Henan province were reported.A 9p trisomy was detected by chromosomal analysis.The proband in family 1 was also diagnosed with epilepsy.Conventional GTG-banded chromosome analysis in the proband of family 1 showed 46,XY,-21,+der(21),t(9; 21).His father and uncle's karyotypes revealed a balanced translocation,46,XY,t(9; 21),and his mother's karyotype was normal.The abnormal chromosome 21 was a derivative chromosome 21 inherited from his father.Thus,the karyotype of proband in family 1 was 46,XY,-21,+der(21),t(9;21 ) pat.The proband in family 2 had refractoriness eczema except for 9p trisomy symptoms.The karyotype was 46,XY,+der (5),t(5;9).His mother's karyotype revealed a balanced translocation,46,XY,t(5; 9) and his father's karyotype was normal.The karyotype of proband in family 2 was 46, XY,+der(5),t(5;9) mat.Further clinical investigation found that there were other individuals with epilepsy disease in family 1.Karyotype analysis found that they all had normal karyotype.In family 2,all individuals had no refractoriness eczema disease except for the proband.To identify the precisely breakpoints,FISH analysis and DNA marker analysis were performed.FISH analysis also showed that the proband in family 1 carried partial 9p trisomy.Molecular genetic analysis defined the precise breakpoint of family 1 on chromosome 9p between markers D9S1846 and D9S171,an interval of about 2.9 Mb on 9p21.3 and the precise breakpoint on chromosome 9p of family 2 between markers D9S1679 and D9S1870,an interval of about 2.7 Mb on 9p21.3.The precise karyotypes of probands in these two families are 46,XY,-21,+der(21),t(9;21)(p21.3;q22.3) pat, and 46,XY,+der(5),t(5;9)(p15.3;p21.3) mat.Although the 9p duplicated region spanned a similar region of 24.4/24.7 Mb(9p21.3 to 9pter),the patients in the two families had a different clinical symptom besides the clinical findings of partial trisomy 9p. These results implicated that trisomy 9p was associated with mental retardation,and that there may be a genomic duplication on chromosome 9pter→9p21.3 responsible for mental retardation and mild facial anomaly.
All these results have clinical implications as they provide valuable information for genetic testing and counseling as well as development of future therapeutic strategies for management of inherited neurogenetic disorders.These studies also provide insights into the pathophysiology of congenital neurogenetic diseases.
癫痫是一种常见的慢性脑部疾病,由多种病因引起的慢性脑功能障碍综合征,具有发作性、复发性和自然缓解性的特点。据估计,癫痫患者约占世界人口的0.5-1%,极大危害人类健康。根据遗传方式可将其分为四大类:单基因遗传病、多基因病遗传病、染色体畸变遗传病、线粒体遗传病。该病又呈现出高度临床表现异质性和遗传异质性。家族性基底节脑血管钙化又称Fahr病,是一种神经系统锥体外系遗传病,伴随癫痫、运动障碍和智力、意识障碍等发生,大多数家系表现为常染色体显性遗传方式,也有常染色体隐性遗传和性染色体遗传的报道,具有广泛的遗传异致性。智力障碍,也称精神发育迟缓是指18岁以前发育阶段由于遗传因素、环境因素和社会心理因素等各种原因所引起,临床表现为智力明显低下和社会适应能力缺陷为主要特征的一组疾病。许多染色体病伴随智力障碍的发生。
(1)在一个来自中国河南的常染色体显性遗传小儿癫痫家系中,通过连锁分析排除所有已知癫痫致病基因和已知位点,对该家系进行全基因组扫描工作,将该家系的致病基因定位在3号染色体长臂上位于D3S3656和D3S1232标记之间大约10.7Mb的区域(3q26.2—q26.33,所获得的两点最大LOD值是4.13)。这是一个新的癫痫致病基因位点。在定位区段内,共有24个已知基因和24个已知的EST。利用突变体检测技术,我们分析了此区域内的18个可能的候选基因,但是没有发现与疾病相关突变。由于我们定位了一个新的癫痫致病位点,该项目的进一步研究有望克隆新的癫痫致病基因。
(2)在河南收集并鉴定了一个5代共31名成员的常染色体显性Fahr病大家系,通过连锁分析排除Fahr病已知致病位点14q13.1-q23.1,对该家系进行全基因组扫描工作,将该家系的致病基因定位在8号染色体上两个标记D8S1809和D8S1833之间大约25.0Mb的区域(8p21.2-q11.23),与D8S505紧密连锁,最大两点LOD值是4.10。此位点是世界上第二个Fahr病致病遗传位点。对该区域内的一个在大脑中广泛表达的SNTG1基因进行测序分析,未发现突变。由于目前还没克隆到Fahr病的相关致病基因,所以本研究为进一步克隆到世界上第一个新Fahr病致病基因奠定了基础。
(3)对来自河南的伴随智力障碍、发育迟缓和手、面部轻微畸形患者进行染色体核型分析,发现是9p部分三体综合征。家系1内的先证者除表现出典型的9p部分三体综合征外,同时患有癫痫。经染色体G-显带分析发现家系1内的先证者核型为46,XY,-21,+der(21),t(9;21)。其父亲、伯父为46,XY,t(9;21)平衡易位核型,母亲核型正常,可知异常染色体来自父亲。所以家系1的先证者核型为46,XY,-21,+der(21),t(9;21)pat。而家系2的先证者除表现出典型的9p部分三体综合征外,并伴有皮肤湿疹症状。G显带核型为46,XY,+der(5),t(5;9),其母亲为46,XX,t(5;9)平衡易位核型,父亲核型正常,所以家系2的先证者核型为46,XY,+der(5),t(5;9)mat。进一步的临床调查发现家系1内另有癫痫患者,但G-显带分析发现他们的核型是正常的。而家系2中无其他人有智障及皮肤湿疹症状。利用荧光原位杂交分析进一步证明了核型分析结果。染色体断裂点分析表明,家系1内的9p断裂点位于D9S1846与D9S171之间,大约2.9Mb;而家系2内的9p断裂点位于D9S1870和D9S1679之间,大约2.7Mb。两个先征者的精确核型分别是:46,XY,-21,+der(21),t(9;21)(p21.3;q22.3)pat,46,XY,+der(5),t(5;9)(p15.3;p21.3)mat。虽然两个家系内的患者具有相似的9p复制区域24.4/24.7 Mb(9p21.3 to 9pter),但两个家系患者除都具有典型的9p部分三体综合征外,并伴有独特的临床症状。分析发现9p三体与智力障碍相关,9p21.3→9ter这段区域可能存在与智力发育相关的基因。
所有这些分子细胞遗传学研究为阐明神经系统遗传病的病理学,以及提供更好的遗传咨询和最终发展有效疾病治疗策略提供了有益的帮助。
Genetic disease can be transmitted to offspring by germ cells and caused by instability of genetic materials,including chromosomal aberrations and gene mutations. Genetic disease in the nervous system is not only the most important inherited disorder, but also a very important part of the neurological diseases and medical genetics. Epilepsy and mental retardation are major neurological disorders and have a high incidence.Fahr disease,another neurological disease,has a high disability rate.In this study,a molecular cytogenetic approach was used to study the inherited neurogenetic diseases in order to find the genes or mutations responsible for these diseases. Functional studies on a pathogenic gene will benefit understanding of mechanisms,and could offer a foundation to therapy of these diseases.
Epilepsy is a chronic disorder of the brain and characterized by the imbalance of neurotransmitters and the abnormal discharge of the neuron.The main characteristics are paroxysmal,recurrent and natural relief.The incidence of epilepsy is 0.5-1%. Hereditary epilepsies were divided into four groups such as single-gene disorders, polygene disorders,chromosome disease,and mitochondria disease.The disease shows wide phenotypic and genetic heterogeneity.Familial idiopathic basal ganglia calcification (IBGC,Fahr disease) is another inherited neurologic condition characterized by basal ganglia and extra-basal ganglia brain calcifications,parkinsonism,and neuropsychiatric symptoms.The major pattern of inheritance is autosomal dominant and autosomal recessive,but X-linked inheritance was also found,which demonstrates genetic and clinical heterogeneity of familial IBGC.Mental retardation is defined by significant limitations in intellectual functions and adaptive behaviors that occur before the age of 18 years.The etiology for mental retardation is highly heterogeneous,and involves many cellular pathways and processes.Both genetic defects and environmental insults,alone or in combination,are known to cause cognitive impairment in humans.Many chromosomal diseases are associated with mental retardation.
(1) A four-generation Chinese family with autosomal dominant febrile seizure and epilepsy was studied by genome-wide linkage analysis after exclusion of known loci and genes for epilepsy.Significant linkage was identified with markers on chromosome 3q26.2-26.33 with a maximum pairwise LOD score of 4.13.Fine mapping defined the new genetic locus within a 10.7 Mb region between markers D3S3656 and D3S1232.Our results identified another novel locus on chromosome 3q26.2-26.33.There are 24 candidate genes and EST in the novel locus region respectively.We analyzed 18 candidate genes in this region,but no mutation was found.A new genetic locus was obtained in our study,which provides a framework for future identification of the specific gene responsible for epilepsy.
(2) We characterized a large five-generation Chinese family with Fahr disease,in which 31 family members were used for genome-wide linkage analysis.After exclusion of the unique genetic locus located on chromosome 14q13.1-q23.1,haplotype and two-point LOD analysis had been performed to define the disease gene interval.The Fahr disease locus in the family was mapped to chromosome 8p21.2-q11.23 with the maximum two-point LOD scores of 4.10 for marker D8S505,and the gene was found to be within a 25.0 Mb interval between markers D8S1809 and D8S1833.Mutation analysis of the SNTG1 gene at the locus,which is specifically expressed in the brain,did not reveal a disease causing mutation.To date,the gene responsible for Fahr disease is not found.Our study provides a framework for identification of a first pathogenic gene for Fahr disease.
(3) Two Chinese families with metal retardation and delayed development in Henan province were reported.A 9p trisomy was detected by chromosomal analysis.The proband in family 1 was also diagnosed with epilepsy.Conventional GTG-banded chromosome analysis in the proband of family 1 showed 46,XY,-21,+der(21),t(9; 21).His father and uncle's karyotypes revealed a balanced translocation,46,XY,t(9; 21),and his mother's karyotype was normal.The abnormal chromosome 21 was a derivative chromosome 21 inherited from his father.Thus,the karyotype of proband in family 1 was 46,XY,-21,+der(21),t(9;21 ) pat.The proband in family 2 had refractoriness eczema except for 9p trisomy symptoms.The karyotype was 46,XY,+der (5),t(5;9).His mother's karyotype revealed a balanced translocation,46,XY,t(5; 9) and his father's karyotype was normal.The karyotype of proband in family 2 was 46, XY,+der(5),t(5;9) mat.Further clinical investigation found that there were other individuals with epilepsy disease in family 1.Karyotype analysis found that they all had normal karyotype.In family 2,all individuals had no refractoriness eczema disease except for the proband.To identify the precisely breakpoints,FISH analysis and DNA marker analysis were performed.FISH analysis also showed that the proband in family 1 carried partial 9p trisomy.Molecular genetic analysis defined the precise breakpoint of family 1 on chromosome 9p between markers D9S1846 and D9S171,an interval of about 2.9 Mb on 9p21.3 and the precise breakpoint on chromosome 9p of family 2 between markers D9S1679 and D9S1870,an interval of about 2.7 Mb on 9p21.3.The precise karyotypes of probands in these two families are 46,XY,-21,+der(21),t(9;21)(p21.3;q22.3) pat, and 46,XY,+der(5),t(5;9)(p15.3;p21.3) mat.Although the 9p duplicated region spanned a similar region of 24.4/24.7 Mb(9p21.3 to 9pter),the patients in the two families had a different clinical symptom besides the clinical findings of partial trisomy 9p. These results implicated that trisomy 9p was associated with mental retardation,and that there may be a genomic duplication on chromosome 9pter→9p21.3 responsible for mental retardation and mild facial anomaly.
All these results have clinical implications as they provide valuable information for genetic testing and counseling as well as development of future therapeutic strategies for management of inherited neurogenetic disorders.These studies also provide insights into the pathophysiology of congenital neurogenetic diseases.
引文
[1] Bell GS, Sander JW. The epidemiology of epilepsy: The size of problem. Seizure. 2002,11:306-14
[2] Bird TD. Major patterns of human inheritance: relevance to the epilpsies. Epilepsies. 1994,35 (suppl 1): s2-s6
[3] Pennacchio LA. Mutation in the gene encoding cystatin B in Progressive myclonus epilepsy. Science. 1996,271 (5262): 1731-4
[4] Cock H. Schapira AV1 Mitochondrial DNA mutations and mitochondrial dysfunction in epilepsy1. Epilepsia. 1999,40 (Suppl 3): 33-40
[5] Du W, Bautista JF, Yang H, et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nature Genetics. 2005, 37(7): 733-38
[6] Jones OT. Ca2+ channels and epilepsy. European Journal of Pharmacology. 2002,447:211-25
[7] Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol. 2003, 54(2): 239-43
[8] Shen YM, Wang XF, Wei Q, et al. Evidence for a major susceptibility locus at 11q22. 1-23. 3 in a large Chinese family with pure grand mal epilepsy. Neuro Sci Lett. 2003, 346(3): 133-6
[9] Gourfinkel-An I, Baulac S, Nabbout R, et al. Monogenic idiopathic epilepsies. The Lancet Neurology. 2004, 3: 209-18
[10] Wyllie E, Gupta A, Lachhwani DK. The treatment of epilepsy: principles and practice. Philadelphia, lea&Febiger. 1993
[11] Garrett KM, Duman RS, Saito N, et al. Isolation of a cDNA clone for the alpha subunit of the human GABA-A receptor. Biochem Biophys Res Commun. 1988, 156: 1039-45
[12] Russek, S. J. Evolution of GABA-A receptor diversity in the human genome. Gene. 1999,227(2): 213-22
[13] Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nature Genet. 2002, 31:184-9
[14] Pritchett DB, Sontheimer H, Shivers BD, et al. Importance of a novel GABA-A receptor subunit for benzodiazepine pharmacology. Nature. 1989, 338: 582-5
[15] Wilcox AS, Warrington JA, Gardiner K, et al. Human chromosomal localization of genes encoding the gamma-1 and gamma-2 subunits of the gamma-aminobutyric acid receptor indicates members of this gene family are often clustered in the genome. Proc Nat Acad Sci. 1992, 89: 5857-61
[16] Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic evidence of GABA-A receptor dysfunction in epilepsy: a mutation in the gamma-2-subunit gene. Nature Genet. 2001, 28: 46-48
[17] Wallace RH, Marini C, Petrou S, et al. Mutant GABA-A receptor gamma-2-subunit in childhood absence epilepsy and febrile seizures. Nature Genet. 2001,28:49-52
[18] Ahmed CMI, Ware DH, Lee SC, et al. Primary structure, chromosomal localization, and functional expression of a voltage-gated sodium channel from human brain. Proc Nat Acad Sci. 1992, 89: 8220-4
[19] Berkovic SF, Heron SE, Giordano L, et al. Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann Neurol. 2004, 55: 550-7
[20] Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genet. 2000, 24: 343-5
[21] Malo D, Schurr E, Dorfman J, et al. Three brain sodium channel alpha-subunit genes are clustered on the proximal segment of mouse chromosome 2. Genomics. 1991, 10: 666-72
[22] Baulac S, Gourfinkel-An I, Picard F, et al. A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33. Am J Hum Genet. 1999, 65: 1078-85
[23] Moulard B, Guipponi M, Chaigne D, et al. Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+)on chromosome 2q24-q33. Am J Hum Genet 1999, 65: 1396-40
[24] Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001,68: 1327-32
[25] McClatchey AI, Cannon SC, Slaugenhaupt SA, et al. The cloning and expression of a sodium channel beta-1-subunit cDNA from human brain. Hum Molec Genet. 1993,2:745-9
[26] Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus, a genetic disorder with heterogeneous clinical phenotypes. Brain. 1997, 120: 479-90
[27] Audenaert D, Claes L, Ceulemans B, et al. A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. Neurology. 2003, 61: 854-6
[28] Wallace RH, Wang DW , Singh R, et al. Febrile seizures and generalized epilep syassociated with a mutation in the Na+2 channel B1 subunit gene SCNIB. Nat Genet. 1998,19: 366-70
[29] Singh NA , Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ 2, is mutated in an inherited epilepsy of new borns. Nat Genet. 1998, 18: 25-9
[30] Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998,279:403-6
[31] Ryan SG, Wiznitzer M, Hollman CH, et al. Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity. Ann Neurol. 1991, 29: 469-73
[32] Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nature Genet. 1998, 18:53-55
[33] Anand R, Lindstrom J. Nucleotide sequence of the human nicotinic acetylcholine receptor beta-2 subunit gene. Nucleic Acids Res. 1990, 18: 4272
[34] Anand R, Lindstrom J. Chromosomal localization of seven neuronal nicotinic acetylcholine receptor subunit genes in humans. Genomics. 1992,13: 962-7
[35] De Fusco M, Becchetti A, Patrignani A, et al. The nicotinic receptor beta-2 subunit is mutant in nocturnal frontal lobe epilepsy. Nature Genet. 2000, 26: 275-6
[36] Phillips HA, Favre I, Kirkpatrick M, et al. CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am J Hum Genet. 2001, 68: 225-31
[37] Kalaehikov S, Evgrafov O, Ross B, et al. Mutations in IGI1 cause autosomal-dominant partial epilepsy with auditory features. Nature Genet. 2002, 30: 335-41
[38] Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sireml S, et al. Mutations in the LGI1 / Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Molec Genet. 2002, 11:1119-28
[39] Gu W, Wevers A, Schroder H, et al. The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins. FEBS Lett. 2002, 519:71
[40] Cid LP, Montrose-Rafizadeh C, Smith DI, et al. Cloning of a putative human voltage-gated chloride channel (CLC-2)cDNA widely expressed in human tissues. Hum Molec Genet. 1995,4: 407-13
[41] Haug K, Warnstedt M, Alekov AK, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nature Genet. 2003, 33: 527-32
[42] Phillips HA, Scheffer IE, Berkovic SF, et al. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13. 2. Nature Genet. 1995,10: 117-8
[43] Guerrini R. Idiopathic epilepsy and paroxysmal dyskinesia. Epilepsia. 2001, 42 (Suppl. 3): 36-41
[44] Escayg A, De Waard M, Lee DD, et al. Coding and noncoding variation of the human calcium-channel beta(4)-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000, 66: 1531-9
[45] Greenberg DA, Delgado-Escueta AV, Widelitz H, et al. A locus involved in the expression of juvenile myoclonic epilepsy and of an associated EEG trait may be linked to HLA and BF. (Abstract)Cytogenet. Cell Genet. 1987,46: 623
[46] Pal DK, Evgrafov OV, Tabares P, et al. BRD2 (RING3)is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet. 2003, 73: 261-270
[47] Berkovic SF, Howell RA, Hay DA, et al. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol. 1998,43: 435-45
[48] Greenberg DA, Cayanis E, Strug L, et al. Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. Am J Hum Genet. 2005, 76: 139-46
[49] Dibbens LM, Feng HJ, Richards MC, et al. GABRD encoding a protein for extra- or peri-synaptic GABA-A receptors is a susceptibility locus for generalized epilepsies. Hum Molec Genet. 2004,13: 1315-9
[50] Ishikawa K, Nagase T, Suyama M, et al. Prediction of coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 1998, 5: 169-76
[51] Nikkila H, McMillan DR, Nunez BS, et al. Sequence similarities between a novel putative G protein-coupled receptor and Na(+)/Ca(2+)exchangers define a cation binding domain. Molec Endocr. 2000, 14: 1351-64
[52] Nakayama J, Fu YH, Clark AM, et al. A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. Ann Neurol. 2002, 52: 654-7
[53] Sainz J, Minassian BA, Serratosa JM, et al. Lafora progressive myoclonus epilepsy: narrowing the chromosome 6q24 locus by recombinations and homozygosities. (Letter)Am J Hum Genet. 1997, 61: 1205-09
[54] Ganesh S, Puri R, Singh S, et al. Recent advances in the molecular basis of Lafora's progressive myoclonus epilepsy. J Hum Genet. 2006, 51:1-8
[55] Suzuki T, Delgado-Escueta AV, Aguan K, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nature Genet. 2004, 36: 842-9
[56] Simpson MA, Cross H, Proukakis C, et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet, 2004, 36 (11): 1225-29
[57] Manyam BV. What is and what is not 'Fahr's disease'. Parkinsonism and Related Disorders. 2005, 11: 73-80
[58] Fujita D, Terada S, Ishizu H, et al. Immunohistochemical examination on intracranial calcification in neurodegenerative diseases. Acta Neuropathologica. 2003, 105: 259-64
[59] Preusser M, Kitwoegerer M, Budka H, et al. Bilateral striopallidodentate calcification (Fahr's syndrome)and multiple system atrophy in a patient with longstanding hypoparathyroidism. Neuropathology. 2007, 27(5): 453-6
[60] Sakuma H, Iwata O, Sasaki M. Longitudinal MR findings in a patient with hemimegalencephaly associated with tuberous sclerosis. Brain Dev. 2005, 27(6): 458-61
[61] Günes T, Kurtoglu S, Cetin N, et al. Raine syndrome associated with cytomegalovirus infection. Turk J Pediatr. 2005, 47(1): 89-91
[62] Lago EG, Baldisserotto M, Hoefel Filho JR, et al. Agreement between ultrasonography and computed tomography in detecting intracranial calcifications in congenital toxoplasmosis. Clin Radiol. 2007, 62(10): 1004-11
[63] Lee CW, Choi DY, Oh YG, et al. An infantile case of Sturge-Weber syndrome in association with Klippel-Trenaunay-Weber syndrome and phakomatosis pigmentovascularis. J Korean Med Sci. 2005, 20(6): 1082-4
[64] Sheth RD, Bodensteiner JB. Progressive neurologic impairment from an arteriovenous malformation vascular steal. Pediatr Neurol. 1995, 13(4): 352-4
[65] Sanchetee P, Venkataraman S, Mohan C, et al. Basal ganglia calcification. J Assoc Physicians India. 1999, 47(5): 507-9
[66] Koller WC, Cochran JW, Klawans HL. Calcification of the basal ganglia: computerized tomography and clinical correlation. Neurology. 1979, 29(3): 328-33
[67]Brosaty H,Mitchell P,Luscombe G,et al.Familial idiopathic basal ganglia calcification(Fahr's disease)without neurological,cognitive and psychiatric symptoms is not linked to the IBGC1 locus on chromosome 14q.Hum Genet.2002,110:8-14
[68]Oliveira JRM,Spiteri E,Sobrido MJ,et al.Genetic heterogeneity in familial idiopathic basal ganglia calcification(Fahr disease).Neurology.2004,63:2165-7
[69]Geschwind DH,Loginov M,Stern JM.Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification(Fahr disease).Am J Hum Genet.1999,65:764-72
[70]Smits MG,Gabr(e|¨)els FJ,Thijssen HO,et al.Progressive idiopathic strio-pallidodentate calcinosis(Fahr's disease)with autosomal recessive inheritance:report of three siblings.Eur Neurol.1983,22:58-64
[71]Francis A,Freeman H.Psychiatric abnormality and brain calcification over four generations.J Nerv Ment Dis.1984,172:166-70
[72]段文澜,刘芳,钟绍,等.特发性双侧对称性大脑基底节钙化症伴染色体异常1例.上海医科大学学报.1998,25(4):289-91
[73]Oliveira JRM,Sobrido MJ,Spiteri E,et al.Analysis of candidate genes at the IBGC1 locus associated with idiopathic basal ganglia calcification("Fahr disease").J Mol Neurosci.2007,33:151-4
[74]Sobrido MJ,Geschwind DH.(2002).Genetics of familial idiopathic basal ganglia calcification(FIBGC).In S.-M.Pulst(Ed.),Genetics of movement disorders(pp.443-448).San Diego:Academic Press
[75]Sobrido MJ,Hopfer S,Geschwind DH.(2002).Idiopathic basal ganglia calcification.GeneReviews:Genetic Disease Online Reviews.www.geneclinics.org
[76]WHO.Mental retardation:meeting the challenge,Joint Commission on International Aspects of Mental Retardation.WHO Offset Publication no.86.Geneva:WHO,1986
[77]Weeks DE,Lathrop GM.Polygenic disease:methods for mapping complex disease traits.Trends Genet.1995,11(12):513-9
[78]J.萨姆布鲁克,D.W.拉塞尔 著.分子克隆实验指南.第三版.黄培堂等译.北京:科学出版社,2002
[79]Wallace RH,Berkovic SF,Howell RA,et al.Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21.J Med Genet.1996,33:308-12
[80]Johnson EW,Dubovsky J,Rich SS,et al.Evidence for a novel gene for familial febrile convulsions,FEB2,linked to chromosome 19p in an extended family from the Midwest.Hum Mol Genet.1998,7:63-7
[81]Kugler SL,Stenroos ES,Mandelbaum DE,et al.Hereditary febrile seizures:phenotype and evidence for a chromosome 19p locus.Am J Med Genet.1998,79:354-61
[82]Peiffer A,Thompson J,Charlier C,et al.A locus for febrile seizures (FEB3)maps to chromosome 2q23-24.Ann Neurol.1999,46:671-8
[83]Nakayama J,Hamano K,Iwasaki N,et al.Significant evidence for linkage of febrile seizures to chromosome 5q14-q15.Hum Mol Genet.2000,9:87-91
[84]Nabbout R,Prud'homme JF,Herman A,et al.A locus for simple pure febrile seizures maps to chromosome 6q22-q24.Brain.2002,125:2668-80
[85]Nakayama J,Arinami T.Molecular genetics of febrile seizures.Epilepsy Res.2006,70:190-8
[86]Hedera P,Ma S,Blair MA,et al.Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22.Epilepsia.2006,47:1622-8
[87]Uebele VN,Lagrutta A,Wade T,et al.Cloning and functional expression of two families of beta-subunits of the large conductance calcium-activated K(+)channel.J Biol Chem.2000,275:23211-8
[88]Brenner R,Jegla TJ,Wickenden A,et al.Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits,hKCNMB3 and hKCNMB4.J Biol Chem.2000,275:6453-61
[89]Rao A,Kim E,Sheng M,et al.Heterogeneity in the molecular composition of excitatory postsynaptic sites during development of hippocampal neurons in culture.J.Neurosci.1998,18:1217-29
[90]Kim JH,Liao D,Lau LF,et al.SynGAP:a synaptic RasGAP that associates with the.PSD-95/SAP90 protein family.Neuron.1998 20:683-91
[91]Chen H.J,Rojas-Soto M,Oguni A et al.A synaptic Ras-GTPase activating protein(p135 SynGAP)inhibited by CaM kinase Ⅱ.Neuron 1998 20:895-904
[92]Geschwind DH,Loginov M,Stem JM.Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification(Fahr disease).Am J Hum Genet.1999,65(3):764-72
[93]Eleopm R,Accurti I,Neff W,et al.Unusual case of Fahr syndrome with motoneuron disease.Ital J Neurol Sci.1991,12(6):597-600
[94]Parker CE,Landing BH.Coincidence of Fahr disease and phenylketonuria.J Pediatr.1977,91(2):273-6
[95]肖慧,谷文萍,李小军等.肝豆状核变性合并Fahr病1例报告.临床神经病学杂志.2006,19(5):335
[96]王康,李玲,熊舸等.合并多发性肾结石的Fahr病1例.中国实用内科杂志.2004,24(10):596
[97]朱晓钢,杨建生,张繁之等.Fahr病合并房颤1例.现代诊断与治疗.2001,12(2):126
[98]覃铄慧.Fahr病伴糖尿病一例报告.医学文选.2004,23(5):693
[99]詹青,张桂运,顾勤等.Fahr病伴后交通动脉瘤和多发性颅内血管狭窄一例.中华神经科杂志.2006,39(4):286
[100]周承惇,任南征,张贵昌等.Fahr′s病合并脑萎缩1例报告并文献复习.中国误诊学杂志.2007,7(8):1682-4
[101]蒋雨平,秦芝丸,印美韵等.特发性两侧对称性大脑基底节钙化症.中国神经精神疾病杂志.1983,9(2):95-7
[102]郑燕銮,李志凌,林丽丽等.9号染色体臂间倒位49例分析.中国优生与遗传杂志.2005,13(11):61
[103]Rethoré MO,Larget-Piet L,Abonyi D,et al.4 cases of trisomy for the short arm of chromosome 9.Individualization of a new morbid entity.Ann Genet.1970,13(4):217-32
[104] Zhuang H, Kosboth M, Lee P, et al. Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p. Arthritis Rheum. 2006, 54(5): 1573-9
[105] Sutherland GR, Carter RF, Morris LL. Partial and complete trisomy 9: delineation of a trisomy 9 syndrome. Hum Genet. 1976, 32(2): 133-40
[106] Centerwall WR, Miller KS, Reeves LM. Familial 'partial 9p' trisomy: six cases and four carriers in three generations. J Med Genet. 1976, 13(1): 57-61
[107] Young RS, Reed T, Hodes ME, et al. The dermatoglyphic and clinical features of the 9p trisomy and partial 9p monosomy syndromes. Hum Genet. 1982, 62(1): 31-9
[108] Wilson GN, Raj A, Baker D. The phenotypic and cytogenetic spectrum of partial trisomy 9. Am J Med Genet. 1985, 20 (2): 277-82
[109] Smart RD, Viljoen DL, Fraser B. Partial trisomy 9--further delineation of the phenotype. Am J Med Genet. 1988,31 (4): 947-51
[110] Schnater JM, Schouten-van Meeteren AY, et al. Hepatoblastoma in a patient with a partial trisomy 9p syndrome: a case report. Cancer Genet Cytogenet. 2005, 156(1): 77-9
[111] Tern JM. The epilepsy of trisomy 9p. Neurology. 1996, 47(3): 821-4
[112] Gigli GL, Scalise A, Silvestri G, et al. Clinical case report: multiple idiosyncratic adverse effects of antiepileptic drugs in trisomy 9p. Int J Neurosci. 1996, 87(3-4): 181-9
[113] Ricart J, Pareja IE. Trisomy 9p associated with self-injured behaviour and multiple intractable keloids. J Eur Acad Dermatol Venereol. 2006, 20(8): 1020-1
[114] De Ravel TJ, Fryns JP, Vandriessche J, et al. Complex chromosome re-arrangement 45, X, t(Y;9)in a girl with sex reversal and mental retardation. Am J Med Genet A. 2004, 124(3): 259-62
[115] De Pater JM, Ippel PF, van Dam WM, et al. Characterization of partial trisomy 9p due to insertional translocation by chromosomal (micro)FISH. Clin Genet. 2002, 62(6): 482-7
[116] Sanlaville D, Baumann C, Lapierre JM, et al. De novo inverted duplication 9p21pter involving telomeric repeated sequences. Am J Med Genet. 1999, 83(2): 125-31
[117] Wilson GN, Raj A, Baker D. The phenotypic and cytogenetic spectrum of partial trisomy 9. Am J Med Genet. 1985,20(2): 277-82
[118] Lewandowski RC Jr, Yunis JJ, Lehrke R, et al. Trisomy for the distal half of the short arm of chromosome 9. A variant of the trisomy 9p syndrome. Am J Dis Child. 1976,130(6): 663-7
[119] Angle B, Yen F, Cole CW. Case of partial trisomy 9p and partial trisomy 14q resulting from a maternal translocation: overlapping manifestations of characteristic phenotypes. Am J Med Genet. 1999, 84(2): 132-6
[120] Chen CP, Chang TY, Shih JC, et al. Prenatal diagnosis of the Dandy-Walker malformation and ventriculomegaly associated with partial trisomy 9p and distal 12p deletion. Prenat Diagn. 2002,22(12): 1063-6
[121] Littooij AS, Hochstenbach R, Sinke RJ, et al. Two cases with partial trisomy 9p: molecular cytogenetic characterization and clinical follow-up. Am J Med Genet. 2002,109(2): 125-32
[122] Piram A, Ortolan D, Peres LC, et al. Newborn with malformtions and a comnined duplication of 9pter-q22 and 16q22-qter resulting from unbalanced segregation of a complex maternal translocation. Am J Med Genet A. 2003, 120 (2): 247-52
[123] De Ravel TJ, Fryns JP, Van Driessche J, et al. Complex chromosome re-arrangement 45, X, t(Y;9)in a girl with sex reversal and mental retardation. Am J Med Genet A. 2004,124 (3): 259-62
[124] Ricart J, Pareja IE. Trisomy 9p associated with selfinjured behaviour and multiple intractable keloids. J Eur Acad Dermatol Venereol. 2006, 20(8): 999-1032
[125] Stern JM. The epilepsy of trisomy 9p. Neurology. 1996, 47(3): 821-4
[126] Gigli GL, Scalise A, Silvestri G, et al. Clinical case report: multiple idiosyncratic adverse effects of antiepileptic drugs in trisomy 9p. Int J Neurosci. 1996, 87(3-4): 181-9
[127] Jalbert P, Sele B, Jalbert H. Reciprocal translocations: Away to predict the mode of imbalanced segregation by pachytene-diagram drawing. Hum Genet. 1980, 55(2): 209-22
[128] Haddad BR, Lin AE, Wyandt H, et al. Molecular cytogenetic characterisation of the first familial case of partial 9p duplication (p22p24). J Med Genet. 1996, 33(12): 1045-7
[129] Curry CJ, Stevenson RE, Aughton D, et al. Evaluation ofmental retar2 dation: recommendations of a consensus conference. Am J Med Genet. 1997, 72 (4): 468-77
[130] Glaas IA. X-linked mental retardation. J med Genet. 1991, 28: 361-3
[131] Lehrke RG. A theory of X - linkage of major intellectual traits. Am J Ment Defic. 1972,76:611-5
[132] Lubs H, Chiurazzi P, Arena J, et al. XLMR Genes: update 1999, 83: 237-47
[2] Bird TD. Major patterns of human inheritance: relevance to the epilpsies. Epilepsies. 1994,35 (suppl 1): s2-s6
[3] Pennacchio LA. Mutation in the gene encoding cystatin B in Progressive myclonus epilepsy. Science. 1996,271 (5262): 1731-4
[4] Cock H. Schapira AV1 Mitochondrial DNA mutations and mitochondrial dysfunction in epilepsy1. Epilepsia. 1999,40 (Suppl 3): 33-40
[5] Du W, Bautista JF, Yang H, et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nature Genetics. 2005, 37(7): 733-38
[6] Jones OT. Ca2+ channels and epilepsy. European Journal of Pharmacology. 2002,447:211-25
[7] Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol. 2003, 54(2): 239-43
[8] Shen YM, Wang XF, Wei Q, et al. Evidence for a major susceptibility locus at 11q22. 1-23. 3 in a large Chinese family with pure grand mal epilepsy. Neuro Sci Lett. 2003, 346(3): 133-6
[9] Gourfinkel-An I, Baulac S, Nabbout R, et al. Monogenic idiopathic epilepsies. The Lancet Neurology. 2004, 3: 209-18
[10] Wyllie E, Gupta A, Lachhwani DK. The treatment of epilepsy: principles and practice. Philadelphia, lea&Febiger. 1993
[11] Garrett KM, Duman RS, Saito N, et al. Isolation of a cDNA clone for the alpha subunit of the human GABA-A receptor. Biochem Biophys Res Commun. 1988, 156: 1039-45
[12] Russek, S. J. Evolution of GABA-A receptor diversity in the human genome. Gene. 1999,227(2): 213-22
[13] Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nature Genet. 2002, 31:184-9
[14] Pritchett DB, Sontheimer H, Shivers BD, et al. Importance of a novel GABA-A receptor subunit for benzodiazepine pharmacology. Nature. 1989, 338: 582-5
[15] Wilcox AS, Warrington JA, Gardiner K, et al. Human chromosomal localization of genes encoding the gamma-1 and gamma-2 subunits of the gamma-aminobutyric acid receptor indicates members of this gene family are often clustered in the genome. Proc Nat Acad Sci. 1992, 89: 5857-61
[16] Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic evidence of GABA-A receptor dysfunction in epilepsy: a mutation in the gamma-2-subunit gene. Nature Genet. 2001, 28: 46-48
[17] Wallace RH, Marini C, Petrou S, et al. Mutant GABA-A receptor gamma-2-subunit in childhood absence epilepsy and febrile seizures. Nature Genet. 2001,28:49-52
[18] Ahmed CMI, Ware DH, Lee SC, et al. Primary structure, chromosomal localization, and functional expression of a voltage-gated sodium channel from human brain. Proc Nat Acad Sci. 1992, 89: 8220-4
[19] Berkovic SF, Heron SE, Giordano L, et al. Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann Neurol. 2004, 55: 550-7
[20] Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genet. 2000, 24: 343-5
[21] Malo D, Schurr E, Dorfman J, et al. Three brain sodium channel alpha-subunit genes are clustered on the proximal segment of mouse chromosome 2. Genomics. 1991, 10: 666-72
[22] Baulac S, Gourfinkel-An I, Picard F, et al. A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33. Am J Hum Genet. 1999, 65: 1078-85
[23] Moulard B, Guipponi M, Chaigne D, et al. Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+)on chromosome 2q24-q33. Am J Hum Genet 1999, 65: 1396-40
[24] Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001,68: 1327-32
[25] McClatchey AI, Cannon SC, Slaugenhaupt SA, et al. The cloning and expression of a sodium channel beta-1-subunit cDNA from human brain. Hum Molec Genet. 1993,2:745-9
[26] Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus, a genetic disorder with heterogeneous clinical phenotypes. Brain. 1997, 120: 479-90
[27] Audenaert D, Claes L, Ceulemans B, et al. A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. Neurology. 2003, 61: 854-6
[28] Wallace RH, Wang DW , Singh R, et al. Febrile seizures and generalized epilep syassociated with a mutation in the Na+2 channel B1 subunit gene SCNIB. Nat Genet. 1998,19: 366-70
[29] Singh NA , Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ 2, is mutated in an inherited epilepsy of new borns. Nat Genet. 1998, 18: 25-9
[30] Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998,279:403-6
[31] Ryan SG, Wiznitzer M, Hollman CH, et al. Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity. Ann Neurol. 1991, 29: 469-73
[32] Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nature Genet. 1998, 18:53-55
[33] Anand R, Lindstrom J. Nucleotide sequence of the human nicotinic acetylcholine receptor beta-2 subunit gene. Nucleic Acids Res. 1990, 18: 4272
[34] Anand R, Lindstrom J. Chromosomal localization of seven neuronal nicotinic acetylcholine receptor subunit genes in humans. Genomics. 1992,13: 962-7
[35] De Fusco M, Becchetti A, Patrignani A, et al. The nicotinic receptor beta-2 subunit is mutant in nocturnal frontal lobe epilepsy. Nature Genet. 2000, 26: 275-6
[36] Phillips HA, Favre I, Kirkpatrick M, et al. CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am J Hum Genet. 2001, 68: 225-31
[37] Kalaehikov S, Evgrafov O, Ross B, et al. Mutations in IGI1 cause autosomal-dominant partial epilepsy with auditory features. Nature Genet. 2002, 30: 335-41
[38] Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sireml S, et al. Mutations in the LGI1 / Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Molec Genet. 2002, 11:1119-28
[39] Gu W, Wevers A, Schroder H, et al. The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins. FEBS Lett. 2002, 519:71
[40] Cid LP, Montrose-Rafizadeh C, Smith DI, et al. Cloning of a putative human voltage-gated chloride channel (CLC-2)cDNA widely expressed in human tissues. Hum Molec Genet. 1995,4: 407-13
[41] Haug K, Warnstedt M, Alekov AK, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nature Genet. 2003, 33: 527-32
[42] Phillips HA, Scheffer IE, Berkovic SF, et al. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13. 2. Nature Genet. 1995,10: 117-8
[43] Guerrini R. Idiopathic epilepsy and paroxysmal dyskinesia. Epilepsia. 2001, 42 (Suppl. 3): 36-41
[44] Escayg A, De Waard M, Lee DD, et al. Coding and noncoding variation of the human calcium-channel beta(4)-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000, 66: 1531-9
[45] Greenberg DA, Delgado-Escueta AV, Widelitz H, et al. A locus involved in the expression of juvenile myoclonic epilepsy and of an associated EEG trait may be linked to HLA and BF. (Abstract)Cytogenet. Cell Genet. 1987,46: 623
[46] Pal DK, Evgrafov OV, Tabares P, et al. BRD2 (RING3)is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet. 2003, 73: 261-270
[47] Berkovic SF, Howell RA, Hay DA, et al. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol. 1998,43: 435-45
[48] Greenberg DA, Cayanis E, Strug L, et al. Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. Am J Hum Genet. 2005, 76: 139-46
[49] Dibbens LM, Feng HJ, Richards MC, et al. GABRD encoding a protein for extra- or peri-synaptic GABA-A receptors is a susceptibility locus for generalized epilepsies. Hum Molec Genet. 2004,13: 1315-9
[50] Ishikawa K, Nagase T, Suyama M, et al. Prediction of coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 1998, 5: 169-76
[51] Nikkila H, McMillan DR, Nunez BS, et al. Sequence similarities between a novel putative G protein-coupled receptor and Na(+)/Ca(2+)exchangers define a cation binding domain. Molec Endocr. 2000, 14: 1351-64
[52] Nakayama J, Fu YH, Clark AM, et al. A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. Ann Neurol. 2002, 52: 654-7
[53] Sainz J, Minassian BA, Serratosa JM, et al. Lafora progressive myoclonus epilepsy: narrowing the chromosome 6q24 locus by recombinations and homozygosities. (Letter)Am J Hum Genet. 1997, 61: 1205-09
[54] Ganesh S, Puri R, Singh S, et al. Recent advances in the molecular basis of Lafora's progressive myoclonus epilepsy. J Hum Genet. 2006, 51:1-8
[55] Suzuki T, Delgado-Escueta AV, Aguan K, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nature Genet. 2004, 36: 842-9
[56] Simpson MA, Cross H, Proukakis C, et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet, 2004, 36 (11): 1225-29
[57] Manyam BV. What is and what is not 'Fahr's disease'. Parkinsonism and Related Disorders. 2005, 11: 73-80
[58] Fujita D, Terada S, Ishizu H, et al. Immunohistochemical examination on intracranial calcification in neurodegenerative diseases. Acta Neuropathologica. 2003, 105: 259-64
[59] Preusser M, Kitwoegerer M, Budka H, et al. Bilateral striopallidodentate calcification (Fahr's syndrome)and multiple system atrophy in a patient with longstanding hypoparathyroidism. Neuropathology. 2007, 27(5): 453-6
[60] Sakuma H, Iwata O, Sasaki M. Longitudinal MR findings in a patient with hemimegalencephaly associated with tuberous sclerosis. Brain Dev. 2005, 27(6): 458-61
[61] Günes T, Kurtoglu S, Cetin N, et al. Raine syndrome associated with cytomegalovirus infection. Turk J Pediatr. 2005, 47(1): 89-91
[62] Lago EG, Baldisserotto M, Hoefel Filho JR, et al. Agreement between ultrasonography and computed tomography in detecting intracranial calcifications in congenital toxoplasmosis. Clin Radiol. 2007, 62(10): 1004-11
[63] Lee CW, Choi DY, Oh YG, et al. An infantile case of Sturge-Weber syndrome in association with Klippel-Trenaunay-Weber syndrome and phakomatosis pigmentovascularis. J Korean Med Sci. 2005, 20(6): 1082-4
[64] Sheth RD, Bodensteiner JB. Progressive neurologic impairment from an arteriovenous malformation vascular steal. Pediatr Neurol. 1995, 13(4): 352-4
[65] Sanchetee P, Venkataraman S, Mohan C, et al. Basal ganglia calcification. J Assoc Physicians India. 1999, 47(5): 507-9
[66] Koller WC, Cochran JW, Klawans HL. Calcification of the basal ganglia: computerized tomography and clinical correlation. Neurology. 1979, 29(3): 328-33
[67]Brosaty H,Mitchell P,Luscombe G,et al.Familial idiopathic basal ganglia calcification(Fahr's disease)without neurological,cognitive and psychiatric symptoms is not linked to the IBGC1 locus on chromosome 14q.Hum Genet.2002,110:8-14
[68]Oliveira JRM,Spiteri E,Sobrido MJ,et al.Genetic heterogeneity in familial idiopathic basal ganglia calcification(Fahr disease).Neurology.2004,63:2165-7
[69]Geschwind DH,Loginov M,Stern JM.Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification(Fahr disease).Am J Hum Genet.1999,65:764-72
[70]Smits MG,Gabr(e|¨)els FJ,Thijssen HO,et al.Progressive idiopathic strio-pallidodentate calcinosis(Fahr's disease)with autosomal recessive inheritance:report of three siblings.Eur Neurol.1983,22:58-64
[71]Francis A,Freeman H.Psychiatric abnormality and brain calcification over four generations.J Nerv Ment Dis.1984,172:166-70
[72]段文澜,刘芳,钟绍,等.特发性双侧对称性大脑基底节钙化症伴染色体异常1例.上海医科大学学报.1998,25(4):289-91
[73]Oliveira JRM,Sobrido MJ,Spiteri E,et al.Analysis of candidate genes at the IBGC1 locus associated with idiopathic basal ganglia calcification("Fahr disease").J Mol Neurosci.2007,33:151-4
[74]Sobrido MJ,Geschwind DH.(2002).Genetics of familial idiopathic basal ganglia calcification(FIBGC).In S.-M.Pulst(Ed.),Genetics of movement disorders(pp.443-448).San Diego:Academic Press
[75]Sobrido MJ,Hopfer S,Geschwind DH.(2002).Idiopathic basal ganglia calcification.GeneReviews:Genetic Disease Online Reviews.www.geneclinics.org
[76]WHO.Mental retardation:meeting the challenge,Joint Commission on International Aspects of Mental Retardation.WHO Offset Publication no.86.Geneva:WHO,1986
[77]Weeks DE,Lathrop GM.Polygenic disease:methods for mapping complex disease traits.Trends Genet.1995,11(12):513-9
[78]J.萨姆布鲁克,D.W.拉塞尔 著.分子克隆实验指南.第三版.黄培堂等译.北京:科学出版社,2002
[79]Wallace RH,Berkovic SF,Howell RA,et al.Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21.J Med Genet.1996,33:308-12
[80]Johnson EW,Dubovsky J,Rich SS,et al.Evidence for a novel gene for familial febrile convulsions,FEB2,linked to chromosome 19p in an extended family from the Midwest.Hum Mol Genet.1998,7:63-7
[81]Kugler SL,Stenroos ES,Mandelbaum DE,et al.Hereditary febrile seizures:phenotype and evidence for a chromosome 19p locus.Am J Med Genet.1998,79:354-61
[82]Peiffer A,Thompson J,Charlier C,et al.A locus for febrile seizures (FEB3)maps to chromosome 2q23-24.Ann Neurol.1999,46:671-8
[83]Nakayama J,Hamano K,Iwasaki N,et al.Significant evidence for linkage of febrile seizures to chromosome 5q14-q15.Hum Mol Genet.2000,9:87-91
[84]Nabbout R,Prud'homme JF,Herman A,et al.A locus for simple pure febrile seizures maps to chromosome 6q22-q24.Brain.2002,125:2668-80
[85]Nakayama J,Arinami T.Molecular genetics of febrile seizures.Epilepsy Res.2006,70:190-8
[86]Hedera P,Ma S,Blair MA,et al.Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22.Epilepsia.2006,47:1622-8
[87]Uebele VN,Lagrutta A,Wade T,et al.Cloning and functional expression of two families of beta-subunits of the large conductance calcium-activated K(+)channel.J Biol Chem.2000,275:23211-8
[88]Brenner R,Jegla TJ,Wickenden A,et al.Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits,hKCNMB3 and hKCNMB4.J Biol Chem.2000,275:6453-61
[89]Rao A,Kim E,Sheng M,et al.Heterogeneity in the molecular composition of excitatory postsynaptic sites during development of hippocampal neurons in culture.J.Neurosci.1998,18:1217-29
[90]Kim JH,Liao D,Lau LF,et al.SynGAP:a synaptic RasGAP that associates with the.PSD-95/SAP90 protein family.Neuron.1998 20:683-91
[91]Chen H.J,Rojas-Soto M,Oguni A et al.A synaptic Ras-GTPase activating protein(p135 SynGAP)inhibited by CaM kinase Ⅱ.Neuron 1998 20:895-904
[92]Geschwind DH,Loginov M,Stem JM.Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification(Fahr disease).Am J Hum Genet.1999,65(3):764-72
[93]Eleopm R,Accurti I,Neff W,et al.Unusual case of Fahr syndrome with motoneuron disease.Ital J Neurol Sci.1991,12(6):597-600
[94]Parker CE,Landing BH.Coincidence of Fahr disease and phenylketonuria.J Pediatr.1977,91(2):273-6
[95]肖慧,谷文萍,李小军等.肝豆状核变性合并Fahr病1例报告.临床神经病学杂志.2006,19(5):335
[96]王康,李玲,熊舸等.合并多发性肾结石的Fahr病1例.中国实用内科杂志.2004,24(10):596
[97]朱晓钢,杨建生,张繁之等.Fahr病合并房颤1例.现代诊断与治疗.2001,12(2):126
[98]覃铄慧.Fahr病伴糖尿病一例报告.医学文选.2004,23(5):693
[99]詹青,张桂运,顾勤等.Fahr病伴后交通动脉瘤和多发性颅内血管狭窄一例.中华神经科杂志.2006,39(4):286
[100]周承惇,任南征,张贵昌等.Fahr′s病合并脑萎缩1例报告并文献复习.中国误诊学杂志.2007,7(8):1682-4
[101]蒋雨平,秦芝丸,印美韵等.特发性两侧对称性大脑基底节钙化症.中国神经精神疾病杂志.1983,9(2):95-7
[102]郑燕銮,李志凌,林丽丽等.9号染色体臂间倒位49例分析.中国优生与遗传杂志.2005,13(11):61
[103]Rethoré MO,Larget-Piet L,Abonyi D,et al.4 cases of trisomy for the short arm of chromosome 9.Individualization of a new morbid entity.Ann Genet.1970,13(4):217-32
[104] Zhuang H, Kosboth M, Lee P, et al. Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p. Arthritis Rheum. 2006, 54(5): 1573-9
[105] Sutherland GR, Carter RF, Morris LL. Partial and complete trisomy 9: delineation of a trisomy 9 syndrome. Hum Genet. 1976, 32(2): 133-40
[106] Centerwall WR, Miller KS, Reeves LM. Familial 'partial 9p' trisomy: six cases and four carriers in three generations. J Med Genet. 1976, 13(1): 57-61
[107] Young RS, Reed T, Hodes ME, et al. The dermatoglyphic and clinical features of the 9p trisomy and partial 9p monosomy syndromes. Hum Genet. 1982, 62(1): 31-9
[108] Wilson GN, Raj A, Baker D. The phenotypic and cytogenetic spectrum of partial trisomy 9. Am J Med Genet. 1985, 20 (2): 277-82
[109] Smart RD, Viljoen DL, Fraser B. Partial trisomy 9--further delineation of the phenotype. Am J Med Genet. 1988,31 (4): 947-51
[110] Schnater JM, Schouten-van Meeteren AY, et al. Hepatoblastoma in a patient with a partial trisomy 9p syndrome: a case report. Cancer Genet Cytogenet. 2005, 156(1): 77-9
[111] Tern JM. The epilepsy of trisomy 9p. Neurology. 1996, 47(3): 821-4
[112] Gigli GL, Scalise A, Silvestri G, et al. Clinical case report: multiple idiosyncratic adverse effects of antiepileptic drugs in trisomy 9p. Int J Neurosci. 1996, 87(3-4): 181-9
[113] Ricart J, Pareja IE. Trisomy 9p associated with self-injured behaviour and multiple intractable keloids. J Eur Acad Dermatol Venereol. 2006, 20(8): 1020-1
[114] De Ravel TJ, Fryns JP, Vandriessche J, et al. Complex chromosome re-arrangement 45, X, t(Y;9)in a girl with sex reversal and mental retardation. Am J Med Genet A. 2004, 124(3): 259-62
[115] De Pater JM, Ippel PF, van Dam WM, et al. Characterization of partial trisomy 9p due to insertional translocation by chromosomal (micro)FISH. Clin Genet. 2002, 62(6): 482-7
[116] Sanlaville D, Baumann C, Lapierre JM, et al. De novo inverted duplication 9p21pter involving telomeric repeated sequences. Am J Med Genet. 1999, 83(2): 125-31
[117] Wilson GN, Raj A, Baker D. The phenotypic and cytogenetic spectrum of partial trisomy 9. Am J Med Genet. 1985,20(2): 277-82
[118] Lewandowski RC Jr, Yunis JJ, Lehrke R, et al. Trisomy for the distal half of the short arm of chromosome 9. A variant of the trisomy 9p syndrome. Am J Dis Child. 1976,130(6): 663-7
[119] Angle B, Yen F, Cole CW. Case of partial trisomy 9p and partial trisomy 14q resulting from a maternal translocation: overlapping manifestations of characteristic phenotypes. Am J Med Genet. 1999, 84(2): 132-6
[120] Chen CP, Chang TY, Shih JC, et al. Prenatal diagnosis of the Dandy-Walker malformation and ventriculomegaly associated with partial trisomy 9p and distal 12p deletion. Prenat Diagn. 2002,22(12): 1063-6
[121] Littooij AS, Hochstenbach R, Sinke RJ, et al. Two cases with partial trisomy 9p: molecular cytogenetic characterization and clinical follow-up. Am J Med Genet. 2002,109(2): 125-32
[122] Piram A, Ortolan D, Peres LC, et al. Newborn with malformtions and a comnined duplication of 9pter-q22 and 16q22-qter resulting from unbalanced segregation of a complex maternal translocation. Am J Med Genet A. 2003, 120 (2): 247-52
[123] De Ravel TJ, Fryns JP, Van Driessche J, et al. Complex chromosome re-arrangement 45, X, t(Y;9)in a girl with sex reversal and mental retardation. Am J Med Genet A. 2004,124 (3): 259-62
[124] Ricart J, Pareja IE. Trisomy 9p associated with selfinjured behaviour and multiple intractable keloids. J Eur Acad Dermatol Venereol. 2006, 20(8): 999-1032
[125] Stern JM. The epilepsy of trisomy 9p. Neurology. 1996, 47(3): 821-4
[126] Gigli GL, Scalise A, Silvestri G, et al. Clinical case report: multiple idiosyncratic adverse effects of antiepileptic drugs in trisomy 9p. Int J Neurosci. 1996, 87(3-4): 181-9
[127] Jalbert P, Sele B, Jalbert H. Reciprocal translocations: Away to predict the mode of imbalanced segregation by pachytene-diagram drawing. Hum Genet. 1980, 55(2): 209-22
[128] Haddad BR, Lin AE, Wyandt H, et al. Molecular cytogenetic characterisation of the first familial case of partial 9p duplication (p22p24). J Med Genet. 1996, 33(12): 1045-7
[129] Curry CJ, Stevenson RE, Aughton D, et al. Evaluation ofmental retar2 dation: recommendations of a consensus conference. Am J Med Genet. 1997, 72 (4): 468-77
[130] Glaas IA. X-linked mental retardation. J med Genet. 1991, 28: 361-3
[131] Lehrke RG. A theory of X - linkage of major intellectual traits. Am J Ment Defic. 1972,76:611-5
[132] Lubs H, Chiurazzi P, Arena J, et al. XLMR Genes: update 1999, 83: 237-47