The first mutations described in PINK1 were homozygous. More recently, heterozygous mutations have been reported but the role of heterozygosity in disease pathogenesis is still debated. We describe two unrelated cases with PINK1 mutations (homozygous nonsense and heterozygous missense) that highlight issues regarding the role of heterozygous mutations and the utility of genetic screening in patient care.
"The first reported PINK1 mutations, G309D and the truncation mutant W437X, were identified in patients of Spanish and Italian origin, respectively (Valente et al., 2004a). Over 20 pathological mutations have now been identified in PINK1 varying from point mutations, truncations and whole gene heterozygous deletions (Klein et al., 2006, Marongiu et al., 2007, Zadikoff et al., 2006), which between them account for between 1–9% of cases with early onset parkinsonism (Healy et al., 2004, Li et al., 2005, Rohe et al., 2004, Tan et al., 2006, Tan et al., 2005, Valente et al., 2004b). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in parkin, PTEN-induced kinase 1 (PINK1) and DJ-1 can all cause autosomal recessive forms of Parkinson's disease. Recent data suggest that these recessive parkinsonism-associated genes converge within a single pathogenic pathway whose dysfunction leads to the loss of substantia nigra pars compacta neurons. The major common functional effects of all three genes relate to mitochondrial and oxidative damage, with a possible additional involvement of the ubiquitin proteasome system. This review highlights the role of the mitochondrial kinase, PINK1, in protection against mitochondrial dysfunction and how this might relate to loss of substantia nigra neurons in recessive parkinsonism.
The international journal of biochemistry & cell biology 11/2009; 41(10):2025-35. DOI:10.1016/j.biocel.2009.02.018 · 4.05 Impact Factor
"iated with psychiatric problems , dementia , and dystonia at onset similar to those with parkin mutations ( Hatano et al . 2004b ) . Furthermore , several screening results imply that a single heterozygous mutation contributes to the development of PD ( Abou - Sleiman et al . 2006 ; Djarmati et al . 2006 ; Hedrich et al . 2006 ; Tan et al . 2006 ; Zadikoff et al . 2006 ) . The clinical features of heterozygous patients are more similar to sporadic PD and old - age onset than those of homozygous patients ( Bonifati et al . 2005 ) . Patients with a single heterozygous PINK1 mutation show low myocardial 123 I meta - iodobenzylguanidine uptake , whereas those with homozygous PINK1 mutations have normal up"
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is one of the most common movement disorders caused by the loss of dopaminergic neuronal cells. The molecular mechanisms underlying neuronal degeneration in PD remain unknown; however, it is now clear that genetic factors contribute to the pathogenesis of this disease. Approximately, 5% of patients with clinical features of PD have clear familial etiology, which show a classical recessive or dominant Mendelian mode of inheritance. Over the decade, more than 15 loci and 11 causative genes have been identified so far and many studies shed light on their implication in not only monogenic but also sporadic form of PD. Recent studies revealed that PD-associated genes play important roles in cellular functions, such as mitochondrial functions, ubiquitin-proteasomal system, autophagy-lysosomal pathway and membrane trafficking. Furthermore, the proteins encoded by PD-associated genes can interact with each other and such gene products may share a common pathway that leads to nigral degeneration. However, their precise roles in the disease and their normal functions remain poorly understood. In this study, we review recent progress in knowledge about the genes associated with familial PD.
Journal of Neurochemistry 09/2009; 111(5):1075-93. DOI:10.1111/j.1471-4159.2009.06403.x · 4.28 Impact Factor
" . heterozygous state of subjects carrying PINK-1 mutations does not generally evolve towards the disease, in some cases it does albeit with a later onset  . This would suggest that dysfunction of PINK1 may promote the disease in combination with other acquired or inherited defect(s). "
[Show abstract][Hide abstract] ABSTRACT: This paper covers genetic and biochemical aspects of mitochondrial bioenergetics dysfunction in hereditary neurological disorders associated with complex I defects. Three types of hereditary complex I dysfunction are dealt with: (i) homozygous mutations in the nuclear genes NDUFS1 and NDUFS4 of complex I, associated with mitochondrial encephalopathy; (ii) a recessive hereditary epileptic neurological disorder associated with enhanced proteolytic degradation of complex I; (iii) homoplasmic mutations in the ND5 and ND6 mitochondrial genes of the complex, coexistent with mutation in the nuclear PINK1 gene in familial Parkinsonism. The genetic and biochemical data examined highlight different mechanisms by which mitochondrial bioenergetics is altered in these hereditary defects of complex I. This knowledge, besides clarifying molecular aspects of the pathogenesis of hereditary diseases, can also provide hints for understanding the involvement of complex I in sporadic neurological disorders and aging, as well as for developing therapeutical strategies.
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