PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism.
ABSTRACT We analyzed the PINK1 gene in 58 patients with early-onset Parkinsonism and detected the homozygous mutation W437X in 1 patient. The clinical phenotype was characterized by early onset (22 years of age), good response to levodopa, early fluctuations and dyskinesias, and psychiatric symptoms. The mother, heterozygote for W437X mutation, was affected by Parkinson's disease and 3 further relatives were reported affected, according to an autosomal dominant transmission.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Parkinson¿s disease (PD) is one of the major neurodegenerative disorders. Mitochondrial malfunction is implicated in PD pathogenesis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1), a serine/threonine kinase, plays an important role in the quality control of mitochondria and more than 70 PINK1 mutations have been identified to cause early-onset PD. However, the regulation of PINK1 gene expression remains elusive. In the present study, we identified the transcription start site (TSS) of the human PINK1 gene using switching mechanism at 5¿end of RNA transcription (SMART RACE) assay. The TSS is located at 91 bp upstream of the translation start site ATG. The region with 104 bp was identified as the minimal promoter region by deletion analysis followed by dual luciferase assay. Four functional cis-acting nuclear factor kappa-light-chain-enhancer of activated B cells (NF¿B)-binding sites within the PINK1 promoter were identified. NF¿B overexpression led to the up-regulation of PINK1 expression in both HEK293 cells and SH-SY5Y cells. Consistently, lipopolysaccharide (LPS), a strong activator of NF¿B, significantly increased PINK1 expression in SH-SY5Y cells. Taken together, our results clearly suggested that PINK1 expression is tightly regulated at its transcription level and NF¿B is a positive regulator for PINK1 expression.Molecular brain. 08/2014; 7(1):57.
- [Show abstract] [Hide abstract]
ABSTRACT: Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2014; · 3.23 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson's disease. Recent works have suggested that loss of mitochondrial membrane potential stabilizes PINK1 and that accumulated PINK1 recruits Parkin from the cytoplasm to mitochondria for elimination of depolarized mitochondria, which is known as mitophagy. In this study, we found that PINK1 forms a complex with SARM1 and TRAF6, which is important for import of PINK1 in the outer membrane and stabilization of PINK1 on depolarized mitochondria. SARM1, which is known to be adaptor protein for Toll-like receptor, bound to PINK1 and promoted TRAF6-mediated lysine-63 chain ubiquitination of PINK1 at lysine 433. Down-regulation of SARM1 and TRAF6 abrogated accumulation of PINK1 followed by recruitment of Parkin to damaged mitochondria. Some pathogenic mutations of PINK1 reduce the complex formation and ubiqutination. These results indicate that the association of PINK1 with SARM1 and TRAF6 is an important step for mitophagy.Molecular biology of the cell 07/2013; · 5.98 Impact Factor