Mutational analysis of the parkin gene in Chinese patients with Parkinson's disease

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Mutational analysis of the parkin gene in Chinese patients with Parkinson's disease


Author: Tam, Ka-wa
Title: Mutational analysis of the parkin gene in Chinese patients with Parkinson's disease
Degree: M.Sc.
Year: 2001
Subject: Parkinson's disease
Hong Kong Polytechnic University -- Dissertations
Department: Multi-disciplinary Studies
Dept. of Nursing and Health Sciences
Pages: xi, 84 leaves : ill. (some col.) ; 30 cm
Language: English
InnoPac Record:
Abstract: Parkinson's disease (PD) is a common slowly progressive neurodegenerative disorder. PD patients present clinical symptoms such as tremor, rigidity, slowness of movement and postural instability. But the etiology and pathogenesis remains poorly understood. The molecular mechanism of the pathogenesis of PD is studied through the identification of genes associated with rare forms of familial PD. Recently, mutations in a novel gene, parkin, are found to be a major cause of the autosomal recessive form of juvenile parkinsonism and early or young onset Parkinson's disease (YOPD). Mutations of the parkin gene including exon rearrangements and point mutations were found in different ethnic populations. Up to now, no study has yet been performed to investigate point mutation of all exons of the parkin gene in Chinese. In this study, we used polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis to detect any homozygous exonic deletion and point mutation in the parkin gene of 20 classical and 7 young onset Parkinson's disease patients. No homozygous exonic deletion was found in patients and normal controls. Nine base substitutions were identified. Three were known polymorphisms: IVS3-20C↙T, G60lA (Ser167Asn) and G1239C (Val380Leu). Other five were new polymorphisms including G520A (Arg140Lys), A1287G (Arg396Gly), C356T, G620A and C1514A. C356T and G620A were silent mutations whereas C1514A was in the non-coding sequence of exon 12. A new heterozygous missense mutation G951C (Gly284Arg) was found in a young onset Parkinson's disease patient. This mutation changed a conserved amino acid in the parkin protein. In addition, it was not found in more than 100 control samples. Recently, the Thr240Arg mutation, within RING-finger motif R1 of the parkin protein, was demonstrated to fail to interact with E2 ubiquitin conjugating enzyme and reduce E3 ubiquitin-protein ligase activity. The mutation G951C was also within the RING-finger motif R1 of the parkin protein, which may be important for the function of E3 ubiquitin-protein ligase to ubiquitination. Therefore, it is worthwhile to further investigate the effect of G951C mutation on YOPD. A common polymorphism was found in the homopolymer T region of intron 2 but was not characterized due to slippage effect in direct sequencing. Racial variation in allele frequency was demonstrated in two polymorphisms in the parkin gene. The frequency of allele A of G601A polymorphism was 0.03 in Australian but 0.36 to 0.44 in South-East Asian and 0.44 in this study; and the frequency of allele C of G1239C polymorphism was about 0.16 in Caucasian, 0.06 in Taiwanese, 0.02 in Japanese and 0.062 in this study. And our study found that the allele and genotype frequencies of these two polymorphisms were not significantly difference among Chinese patients with classical, young onset Parkinson's disease and normal controls except the genotype frequencies of the polymorphism G1239C was significantly different between Chinese patients with classical PD and control groups. It is needed to confirm because only one PD patient with homozygous mutation was found in this study. Besides two well-known polymorphisms, the frequencies of minor allele of two newly identified polymorphisms A1287G (Arg396Gly) and C1514A were 0.029 and 0.096 respectively. In addition, there was no significant difference in allele and genotype frequencies of these polymorphisms among PD patients and controls. Other mutations found are rare polymporhisms. C356T was found in one PD patient, and G520A and G620A were found in two different control samples.

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