Genetic Characteristic And Gene Mutation Detection In One Familial Parkinson Disease

Parkinson's disease (PD)is a common neurodegenerative diseases in elderly, to date, the exact etiology and pathogenesis of PD are still unclear, research shows that genetic, environmental, and interaction of multiple factors such as aging lead to PD occurred. The majority of patients with Parkinson disease as sporadic cases, about 10% to 15% of PD patients had positive family history in foreign report, our epidemiological survey in Guangdong found that 8.9% of patients had positive family history. When in 1997, the first single-disease genes of PD (α-synuclein, PARK1) discovered and with the development of molecular biology, genetic factors became a focus of research to scholars over the past decade. So far, at least reported 13 genes associated with familial Parkinson's disease, the location ,function and protein products of these genes has provided important clues to the study of the pathogenesis for PD, such as PARK1 the gene expression product isα-synuclein, it is the main component of Lewy bodies, PARK5 gene which is UCHL-1, whose mutation causes dysfunction of the degradation of ubiquitin-proteasome system, leading to abnormal protein aggregation, which led to the occurrence of PD. Currently there are few reports and research about PD pedigrees in our country, especially for the pedigrees which have multi-generation patients, at present the features of gene mutation in china are unclear. Our country have large population, so the PD patients are also many, so the investigation and gene loci study for familial PD has great significance.The investigation of this issue is a PD family from Baishan city of Jilin Province, to investigate the family, ruled out the disease groups factors such as environmental, diagnosed with idiopathic PD pedigrees. After the family members signed informed consent, then we began to collect clinical data, for determination of PD and related auxiliary scale inspection, mapping genetic map of the family. A total of four generations of the family of 25 people ,which have 9 patients, accounting for 30% of family members; existing two generations of 21 person, which 6 people had diagnosed with PD,4 people suspected of PD.Each generation have patients, both male and female patients, age <40 years, slow progression, clinical presentation was similar, and many more tremors onset, accompanied by increased muscle tone and motor retardation, with varying degrees of non-motor symptoms such as sleep disturbance and depression in the main; intelligent obvious decline; oral levodopa treatment is effective. The family is a clear genetic relationship, the incidence higher number of autosomal dominant PD pedigrees.Collecting peripheral blood of family members and some spouses ,extract the leukocyte DNA for disease gene location. Ideas for the first experiment using PCR-RFLP and PCR-DNA sequencing method to scan several current common autosomal dominant PD point mutation. If the result is negative, then use the STR fluorescent marker gene linkage analysis to analysis the autosoml dominant PD gene which is known, attempt to mapping the disease gene to a chromosomal region; if the current loci are all negative results, we use the whole genome scan method to location disease gene.After orientation to the specific chromosomal region, select the gene near the loci which associated with PD ,to scan whether mutations exist in this familial PD, and to locate the specific gene mutations in this PD family.First we scan six most common mutations point of autosomal dominant of PD, these gene mutations as PARK1 (A30P and A53T), PARK5 (I93M), PARK8 (R1441G / C, R1441H and G2385R) were detected, all the family members and spouses were obtained negative results, indicating that the family does not exist the six common mutations. Then we use linkage analysis to scan the four gene which known as autosomal dominant PD gene, designed STR polymorphic markers across PARK1, PARK3, PARK5 and PARK8 this four chromosomal loci, and finally we basically exclude PARK1, PARK3, PARK5 chromosomal loci linked with disease genes; Our results suggest that the pathogenic gene of this PD family located on chromosome 12 near the 12q12 locus D12S85 STR polymorphisms, and linkage with D12S1668 some distance from the chain (<10 cM), shows the family of disease genes may be located within the area, while LRRK2 gene near the two STR loci which associated with PD, we speculate, LRRK2 mutation may be a causative gene for the family. We PCR and compared the sequence of the 51 exon of LRRK2 gene in the patients in this family, found that the patient (301,302,303,305,306,405) all have a point mutation in exon 24,the No.3200 nucleotide G change into A, the Arg which is No.1067 protein change into Gln. Further all members of the family PCR amplification and compared on exon 24, found that there are family members of the 307,403,407,409 of the same mutation. Spouses were not found this mutation. Clear that the gene in this family is LRRK2, mutations in the form of Arg1067Gln. The reason of why members who find mutations do not diagnosis, one may consider that the members not reached age of onset, and second, the changes caused by the gene may not completely explicit. In summary, PD caused by the Arg1067Gln clinical manifestations similar to idiopathic PD , the difference is that early onset and slow disease progression.We study the clinical characteristic and mapping the gene mutation in a familial PD, provided a series experience for future genetic study of PD, for the first time found the Arg1067Gln mutation for PD in our county. Further study of the mutations caused changes in the protein function can provide a theoretical basis for the pathogenesis of PD.