A heterozygous effect for PINK1 mutations in Parkinson's disease?

• Published in: Annals of neurology Vol. 60; no. 4; pp. 414 - 419
• Main Authors: Abou-Sleiman, Patrick M., Muqit, Miratul M. K., McDonald, Neil Q., Yang, Yan Xiang, Gandhi, Sonia, Healy, Daniel G., Harvey, Kirsten, Harvey, Robert J., Deas, Emma, Bhatia, Kailash, Quinn, Niall, Lees, Andrew, Latchman, David S., Wood, Nicholas W.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2006; Willey-Liss
• Subjects: Adult; Age of Onset; Aged; Alleles; Biological and medical sciences; Cells, Cultured; Chromosomes - genetics; Computational Biology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Mutational Analysis; Female; Flow Cytometry; Gene Frequency; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Heterozygote; Humans; Male; Medical sciences; Membrane Potentials - physiology; Middle Aged; Mitochondria - physiology; Mutation - physiology; Nervous system (semeiology, syndromes); Neurology; Open Reading Frames - genetics; Parkinson Disease - genetics; Protein Kinases - genetics; Transfection; Nervous system diseases; Central nervous system disease; Parkinson disease; Degenerative disease; Mutation; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.20960

Objective To investigate the significance of PINK1 mutations in sporadic Parkinson's disease (PD). Methods We determined the frequency of PINK1 mutations by direct sequencing in a large series of PD patients with apparently sporadic disease (n = 768). Results Twelve heterozygous mutations were identified, nine in PD patients and three in control subjects. Interpretation Given the difficulty in interpreting the pathogenic significance of the heterozygous mutations that have already been reported in parkin and DJ‐1, we first determined the frequency of heterozygous PINK1 mutations in the general population by sequencing a large number of control subjects (n = 768), then subsequently assessed their functional significance by examining their effects on stress‐induced alterations to the mitochondrial membrane potential (ΔΨm). We demonstrate an enrichment of heterozygous mutations in sporadic PD patients compared with matched control subjects (1.2% in PD vs 0.4% in control subjects). Furthermore, we show that they adversely affect ΔΨm in a similar way to the familial G309D mutation. Although it remains difficult to conclusively demonstrate the pathogenicity of heterozygous mutations, the results of this study and the previously reported subclinical nigrostriatal dysfunction in carriers of heterozygous PINK1 mutations suggest the possibility that these heterozygous mutations are a significant risk factor in the development of later onset PD. Ann Neurol 2006