PINK1 – Young-Onset Parkinson Disease

PTEN-induced kinase 1 (PINK1) encodes a mitochondrial serine/threonine kinase that protects dopaminergic neurons by maintaining mitochondrial integrity and preventing apoptosis. Biallelic loss-of-function variants in PINK1 underlie autosomal recessive early-onset Parkinson disease, often presenting before age 50 with parkinsonism and variable cognitive decline.

Initial reports described a novel homozygous single-nucleotide deletion in exon 4 (c.889del (p.Asp297MetfsTer22)) resulting in kinase-domain truncation in two Sicilian brothers with early-onset Parkinson disease and divergent cognitive outcomes (PMID:18329316). Subsequent cohorts identified additional compound heterozygous and homozygous carriers, including one Korean patient with c.1100A>G (p.Asn367Ser) and c.1558_1559del (p.Lys520ArgfsTer2) (PMID:18704525) and one Brazilian patient with an exon 7 homozygous deletion (PMID:19205068).

The variant spectrum encompasses frameshift (e.g., c.889del (p.Asp297MetfsTer22)), nonsense, splice, and missense changes (e.g., c.1100A>G (p.Asn367Ser)), all predicted or shown to abrogate kinase activity. Recurrent missense alleles (p.Gly309Asp, p.Leu347Pro) exhibit reduced stability and impaired enzymatic function. No clear founder variants have been described; carrier frequencies remain low (<0.1%).

In total, four unrelated probands with biallelic PINK1 pathogenic variants across three families provide genetic evidence for autosomal recessive inheritance with segregation in a consanguineous pedigree (two affected siblings) and consistent early-onset parkinsonism (PMID:18329316, PMID:18704525, PMID:19205068). Heterozygous carriers may exhibit increased risk but require further investigation.

Functional assays demonstrate that wild-type PINK1 prevents staurosporine- and MPP(+)-induced neuronal apoptosis by inhibiting cytochrome c release and caspase activation; pathogenic mutations abolish this protection (PMID:16079129). Drosophila pink1 loss-of-function models recapitulate mitochondrial degeneration and dopaminergic neuron loss, rescued by human PINK1 but not by disease-associated mutants (PMID:16818890).

Collectively, PINK1 exhibits a moderate level of clinical validity for young-onset Parkinson disease based on multiple biallelic probands, segregation data, and concordant experimental evidence. Genetic testing for PINK1 should be considered in early-onset parkinsonism to inform diagnosis, management, and genetic counseling.

References

• Parkinsonism & related disorders • 2008 • Identification of the novel D297fsX318 PINK1 mutation and phenotype variation in a family with early-onset Parkinson's disease. PMID:18329316
• Neurogenetics • 2008 • Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. PMID:18704525
• Movement disorders : official journal of the Movement Disorder Society • 2009 • Familial Parkinsonism and early onset Parkinson's disease in a Brazilian movement disorders clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations. PMID:19205068
• The Journal of biological chemistry • 2005 • Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. PMID:16079129
• Proceedings of the National Academy of Sciences of the United States of America • 2006 • Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. PMID:16818890

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