We describe clinical and molecular findings in a genetic isolate from north-eastern Brazil with early-onset Parkinson's disease (PD) and a novel mutation in the parkin gene. Genealogical studies could connect 255 individuals, of whom 15 had PD. Geographic isolation and multiple consanguineous marriages initially suggested an autosomal recessive inheritance for PD in these patients. The available individuals were personally examined, and DNA was obtained from 26 members: ten early-onset PD patients, one case with likely neuroleptic-induced parkinsonism and 15 unaffected relatives. The average age at onset of PD symptoms was 30.8 years (range 12-46). Haplotype analysis revealed homozygosity in the PD patients for markers across the PARK2 locus. Genomic sequencing identified a novel homozygous splice-site parkin mutation (IVS1+1G/ T), which completely co-segregated with the early-onset PD phenotype. cDNA analysis confirmed the total loss of parkin transcript in homozygous mutation carriers, delineating this as a loss-of-function mutation. The case with neuroleptic-induced parkinsonism and 13 of 15 healthy relatives were heterozygous carriers of the mutation. The absence of PD in heterozygous carriers indicates a genuinely recessive nature of this mutation, suggesting that parkin haploinsufficiency is not a relevant risk factor for early- or late-onset PD. However, parkin haploinsufficiency could facilitate the emergence of neuroleptic-induced parkinsonism. The cluster reported here, which to our knowledge is the largest described to date with early-onset PD and parkin mutations, also offers a unique opportunity for the search of modifiers of the parkin-related disease.

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doi.org/10.1007/s10048-005-0017-x, hdl.handle.net/1765/69361
Department of Clinical Genetics

Chien, H., Rohe, C. F., Costa, M. D., Breedveld, G., Oostra, B., Barbosa, E., & Bonifati, V. (2006). Early-onset Parkinson's disease caused by a novel parkin mutation in a genetic isolate from north-eastern Brazil. Neurogenetics, 7(1), 13–19. doi:10.1007/s10048-005-0017-x