Molecular Cytogenetics Study Of Three Kinds Of Hereditary Neurogenetic Diseases

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.