Linkage And Mutation Discovery

The ARPD locus, PARK6, was mapped to a 12.5-centimorgan (cM) region on chromosome 1p35-36 in a large consanguineous Sicilian family (Marsala kindred) (1). Autozygosity mapping of two additional families (one Italian and one Spanish) with ARPD provided additional evidence of linkage to PARK6 and refinement of the critical region to a 3.7 cM interval between markers D1S2647 and D1S1539. Fine mapping of the refined region using single nucleotide polymorphisms (SNPs) further narrowed the interval to 2.8 megabases (Mb), containing approximately 40 genes. These genes were prioritized according to putative expression pattern and function prior to sequencing. Two mutations in the open reading frame (ORF) of the PINK1 gene were identified. The mutations segregated with the disease, were predicted to adversely affect the protein product and were absent in a large cohort of control individuals (2). Taken together, this evidence indicated that the PINK1 mutations were causal of the PD phenotype in the families.

The PINK1 gene comprises eight exons, spanning approximately 18 kb of genomic DNA. It encodes a 581 amino acid protein that contains a mitochondrial targeting motif and a highly conserved kinase domain. The Spanish family carried a homozygous G/A substitution in exon 4, resulting in a G309D missense mutation at a highly conserved residue in the kinase domain. The Italian families carried the same homozygous G/A substitution in exon 7, which results in a nonsense mutation truncating 145 amino acids at the C-terminus. The Italian families were not knowingly related, despite originating from distinct geographical regions, and were later shown to share a haplotype around the PARK6 locus, implying common ancestry.

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