Article

Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism

Sapienza University of Rome, Roma, Latium, Italy
Annals of Neurology (Impact Factor: 11.91). 10/2004; 56(3):427-31. DOI: 10.1002/ana.20247
Source: PubMed

ABSTRACT 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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    • "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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    • "PINK1 gene was originally mapped in a Sicilian family with autosomal recessive parkinsonism (Valente et al., 2001). Subsequently, PINK1 mutations have been associated with early-onset Parkinson's disease in several families and in 2–4% of sporadic early-onset Parkinson's disease, being the second most frequent cause of early-onset Parkinson's disease (Rohe et al., 2004; Chishti et al., 2006; Savettieri et al., 2008; Cazeneuve et al., 2009). Most PINK1 mutations are missense, but gene and exonic rearrangements also have been described (Li et al., 2005; Ibanez et al., 2006; Marongiu et al., 2007; Camargos et al., 2009). "
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    • "A homozygous G309D mutation and a truncating W437X mutation were first identified in consanguineous European PD families [10]. Subsequently , additional autosomal recessive PINK1 mutations, including heterozygote compound mutations at E240K and L489P, were identified in other PD families [54] [55] [56] [57]. The possibility of PINK1 haploinsufficiency as a risk factor in sporadic PD has also been raised [58] [59] [60]. "
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