Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism

Sapienza University of Rome, Roma, Latium, Italy
Annals of Neurology (Impact Factor: 9.98). 10/2004; 56(3):427-31. DOI: 10.1002/ana.20247
Source: PubMed


Two homozygous mutations in the PINK1 gene, encoding a mitochondrial putative protein kinase, recently have been identified in families with PARK6-linked, autosomal recessive early-onset parkinsonism (AREP). Here, we describe a novel homozygous mutation (1573_1574 insTTAG) identified in an AREP patient, which causes a frameshift and truncation at the C-terminus of the PINK1 protein, outside the kinase catalytic domain. The clinical phenotype includes early-onset (28 years) parkinsonism, foot dystonia at onset, good levodopa response, slow progression, early levodopa-induced dyskinesias, and sleep benefit, thereby resembling closely parkin-related disease. These findings confirm that recessive mutations in PINK1 cause early-onset parkinsonism and expand the associated clinical phenotype.

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    • "Mutations in the mitochondrial serine/threonine kinase PTEN-induced putative kinase 1 (PINK1) correlate with disease incidence (Valente et al., 2004a). Many of these mutations cluster in the kinase domain of PINK1 and result in a non-functional protein (Hatano et al., 2004; Rohe et al., 2004; Valente et al., 2004a,b; Sha et al., 2010). Deficiencies of pink1 in Drosophila lead to changes in mitochondrial morphology, increased sensitivity to oxidative stress and reduced viability (Clark et al., 2006). "
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    Frontiers in Aging Neuroscience 04/2012; 4(article 5):5. DOI:10.3389/fnagi.2012.00005 · 4.00 Impact Factor
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    • "Several of the reported mutations of PINK1 are located in the kinase domain [38, 46–48] and altered phosphorylation of target proteins probably represents a key pathogenic mechanism. The phosphorylation of mitochondrial proteins is considered pivotal to the regulation of respiratory activity in the cell and to signalling pathways leading to apoptosis, as well as for other vital mitochondrial processes. "
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    • "Point mutations in the PTEN-induced kinase or PINK1 gene, a putative mitochondrial kinase at the PARK6 locus, are the second most frequently occurring cause of autosomal recessively inherited early-onset PD (Valente et al. 2001,2004; Hatano et al. 2004; Rogaeva et al. 2004; Rohe et al. 2004; Bonifati et al. 2005; Bender et al. 2006; Ibanez et al. 2006). PINK1 is present throughout the brain and localizes to mitochondria where it is thought to protect against mitochondrial dysfunction (Gandhi et al. 2006). "
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