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Neurogenetics

Several mutations of mitochondrial DNA (mtDNA) and polymorphisms of the debrisoquine 4-hydroxylase gene (CYP2D6) have been associated with an increased susceptibility to Parkinson's disease (PD). We have studied 21 neuropathologically verified cases of PD and 89 controls. Genomic DNA was extracted from formalin-fixed, paraffin-embedded brain tissue as well as from freshly frozen tissue blocks and amplified using the polymerase chain reaction. PCR products were analyzed by restriction enzyme digestion and direct non-radioactive cycle sequencing. Degrees of mtDNA heteroplasmy were determined using laser densitometry. Ratios of mtDNA carrying the 4977 bp "common deletion" were quantified by competitive PCR. 4 out of 21 PD brains (5/77 controls) showed a heteroplasmic mtDNAG5460A transition which affects the ND2 subunit gene of complex I. Degrees of heteroplasmy for this point mutation ranged from less than 5 to more than 95%. One PD brain was homoplasmic for the mtDNAA4336G transition affecting the mitochondrial tRNAGln. In contrast, levels of the 4977 bp deletion were not increased in the substantia nigra of PD brains. Allelic frequencies at the CYP2D6 locus (CYP2D6G1934A and CYP2D6C2938T) were comparable in PD cases and controls. One PD brain was homozygous for the CYP2D6C2938T allele. Our results show that patients with Lewy-body parkinsonism exhibit genetic heterogeneity at candidate susceptibility loci. Our findings are in line with the concept that a definable number of interindividually variable genetic defects may confer increased susceptibility to PD. Systematic sequencing studies will help to clarify whether mitochondrial point mutations are responsible for the complex I defect observed in PD.

Supported by the Deutsche Forschungsgemeinschaft (Gerhard Hess-Programm).

Headings
Parkinson's disease (PD)
NADH dehydrogenase
CYP2D6 genotypes

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