We investigated 11 consanguineous families comprising 17 affected with recessively inherited young-onset parkinsonism for mutations both in the parkin and PINK1 gene.
Here, we describe a novel homozygous mutation (Q126P), identified in two affected German sisters with a clinical phenotype typical for PINK1-associated parkinsonism.
To investigate a possible association of mutations in the PTEN-induced putative kinase 1 (PINK1) gene with psychiatric disorders in a large family with monogenic parkinsonism.
These findings further expand the clinical spectrum of PINK1-related parkinsonism to include late onset, typical PD, and underline the existing difficulties in discriminating between mendelian parkinsonism and idiopathic PD.
In the present study we analysed fibroblasts from a patient carrying the homozygous mutation p.W437X in the PTEN-induced kinase 1 (PINK1), which manifested a very early onset parkinsonism.
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.
These results underscore the relevance of the PINK1/Parkin-mediated mitochondrial quality control pathway in primary neurons and shed further light on the underlying mechanisms of the PINK1 and Parkin pathogenic mutations that predispose Parkinsonism in vivo.
Mutations in the PARK2 and PARK6 genes, coding for the cytosolic E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1 [phosphatase and tensin homologue (PTEN)-induced putative kinase 1], lead to clinically similar early-onset Parkinsonian syndromes.
These findings indicate that PINK1 mutation might modify parkin mutation-positive Parkinsonism, and PINK1 mutations might be associated with psychiatric disorders.
Four PINK1 homozygous mutations, three novel (Q129X, Q129fsX157, G440E, and one previously reported; Q456X), segregate with parkinsonism in 46 individuals in 14 of 92 families (15%).