The Research About Clinical Feature And Gene Mutation Detection In A Chinese Parkinson’s Disease Family

Background and Objective：Parkinson’s disease (PD) is the most commonly degenerative disorder of thecentral nervous system middle aged and elderly people. Its clinical fetures aretatic tremor, rigidity and dyskinesia, and abnormal posture and pace. The etiologyand pathogenesis of PD is still not completely clear. Recently research shows thatgenetic, environmental, and interaction of multiple factors such as aging relatedto PD. The majority of patients with Parkinson disease are sporadic cases.According to foreign report, there were10%to15%of PD patients with positivefamily history, meanwhile the domestic epidemiological survey in Guangdongprovince found that8.9%of patients had positive family history. In1997, the firstsingle-disease gene related to PD (α-synuclein, PARK1) was discovered. The pastdecade has seen tremendous progress in our understanding of the genetic basis ofPD. Up to date, more than16genes reportedly associated with familialParkinson’s disease, the mutation of the leucine-rich repeat kinase2gene (LRRK2) is the most commonly detected genetic determinant of Parkinson’sdisease (PD). However, the specific role of the LRRK2genetic lesion in theoccurrence of autosomal dominant family PD remains elucidated. Currently thereare few reports about PD pedigrees in China, especially for the pedigrees whichhave multi-generation patients. For the large population of PD patients in China,it is very important to study the familial PD related gene and its function whichwill provide the evidences and clues for the etiology, mechanism and geneticsinterrogation of PD.Subjects and Methods：In this study, we report a large Chinese LRRK2-related PD family with33members of four generations. Primary epidemiological investigation indicatedthat it is an idiopathic PD pedigree after rule out the environmental factors whichcause the group onset of PD. After the family members signed informed consent,clinical data were prudently collected. A total of four generations of the family of33people, which have13patients (7males,6females;4decesed), and6suspicious (1male and5females), accounting for57%of family members. Patients distribute in each generation without sex bias, age of onset renge from33to53years old, slow progression, similar clinical presentation, and mostlyonset with tremors, accompanied by increased muscle tone and motor retardation,with varying degrees of non-motor symptoms such as conspitation, hyposphresia,sleep disorder and depression; without obverse intelligent decline; oral levodopatreatment is effective. In conclusion, this family, with clear genetic origins,belongs to an autosomal dominant PD pedigrees bared large portion of patients.Peripheral blood specimens were drew from11selected subjects forgenomic DNA analyze. Genomic DNA was extracted following the standardprotocol. Firstly, we use PCR-RFLP and PCR-DNA sequencing method to screenseveral current common autosomal dominant PD related gene mutation. We havescreened the most commonly reported PD-related mutations, such as PARK1-E3,PARK1-E4, PARK5-E4, and LRRK2-E31. We detect no mutation in these genes,except for LRRK2-E48, which has been reported to be associated with high PDrisk in Han Chinese. To further confirm the mutation, we designed a pair ofmismatch primers to amplify LRRK2-E48with one nucleotide change so that itcan be recognized by HaeIII, whereas the enzyme cannot cut up the PCR production if the patient has the G2385R mutation. The data from the restrictionenzyme digestion are consistent with DNA sequencing.Results：In this study, there were3cases with the G2385R (G/Gâ†'G/A) mutation,2afflicted cases of the third generation and1suspicious case of the fourth. The rateof the G2385R mutation among affected members is about50%(2/4), while therate in suspicious patients is20%(1/5). No G2385R mutation was detected inhealthy members. It should be noted that subject411is the daughter of affectedcase307, they both bare the G2385R mutation which suggesting that theinherited pattern is consistent with autosomal inherent disease. Thus, it seems thatthe G2385R mutation penetrated from the ancestor of this large family.Conclusion：This family is an autosomal dominant family PD pedigree, the age of onsetarrenge frome33to53years old. All the patient share similar disease patternsuch as static tremor, rigidity and dyskinesia, the disease progressed slowly, oral levodopa treatment is effective. On the genetic level, LRRK2gene G2385Rmutation is detected in this family which is the first time to be reported in themainland of China.InnovationAnalysis of the clinical characteristics and mapping of their gene mutation inthis PD family, provided a series experience for future genetic study of familialPD. We initially report LRRK2-G2385R-related familial PD in the mainland ofChina which furnished the genetic findings in PD-oriented study field.