Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls.
ABSTRACT Mutations in the parkin gene cause autosomal recessive early-onset parkinsonism. The effect of single heterozygous mutations in parkin is still unclear. The aim of this study was to evaluate the frequency of exonic parkin variants in a case-control study.
The parkin gene was screened for both point mutations and exon rearrangements in 172 French patients with Parkinson disease (PD) and 170 controls from the same population. Patients with single parkin variants were also screened for PINK1, DJ-1 and LRRK2 exon 41 mutations.
10 exonic sequence variations were identified, including 3 known polymorphisms and 7 rare heterozygous variants, 2 of which were novel. There were significantly more rare heterozygous variants in patients (n = 10) with early-onset PD than in controls (n = 2). Screening of PINK1, DJ-1 and LRRK2 exon 41 in the 10 patients heterozygous for parkin failed to identify a second causative mutation.
These results suggest that single parkin mutations increase the risk of early-onset PD, but the possibility of a second parkin mutation cannot be excluded.
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ABSTRACT: Background. and Purpose There is some controversy regarding heterozygous mutations of the gene encoding parkin (PARK2) as risk factors for Parkinson's disease (PD), and all previous studies have been performed in non-Asian populations. Dosage Mutation of PARK2, rather that a point mutation or small insertion/deletion mutation, Was reported to be a risk factor for familial PD; dosage mutation of PARK2 is common in Asian populations. Methods We performed a. gene-dosage analysis of PARK2 using real-time polymerase chain reaction for 189 patients With early-onset PD or familial PP, 00,191 control individuals. In the case of PD patients With heterozygous gene-dosage mutation, we:performed a sequencing analysis to exclude compound heterozygous mutations. The association between heterozygous mutation of PARK2 and PD was tested. Results We identified 4 PD) patients with PARK2 mutations (11.6%). Five patients (2.6%) had compound heterozygous mutations, and 13 patients (6.9%) had a heterozygous mutation. The phase could not be determined in one patient. Three small sequence variations were found in 30 mutated alleles (10.0%). Gene-dosage mutation aceounted for 90% of all of the mutations found. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD patients than in the controls. Conclusions Heterozygous gene-dosage mutation of PARK2 is a genetic risk factor for patients with early-onset or familial PD in Koreans.Journal of Clinical Neurology 07/2014; 10(3):244-8. DOI:10.3988/jcn.2014.10.3.244 · 1.81 Impact Factor
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ABSTRACT: Parkinson's disease (PD) is the second most common progressive neurodegenerative brain disorder after Alzheimer's disease. Due to the complex etiology of PD, there is possibility that single nucleotide polymorphisms (SNP) in PARKIN gene could be associated with the disease and lead to the pathogenesis by genoenvironmental interactions. Role of PARKIN polymorphisms as risk factors varies in different populations among various ethnic groups. Indian populations, known for their rich diversity, are not included in the genotyping of single nucleotide polymorphisms in the global survey for all the genes associated with PD. Further detailed study in this field will give a greater insight to analyze the haplotypic and Linakage Disequilibrium (LD) and decipher the pathogenesis of PD patterns in this region. A total of 1000 individuals belonging to ten ethnic populations of India were included in the present study. Five PARKIN gene polymorphisms (rs1801474, rs72480421, rs1801582, rs1801334 and rs35125035) were screened by PCR and sequencing. The present study shows that the rs72480421 (His200Gln) is monomorphic for all populations. Five major haplotypes accounted for almost all chromosomes (90-98%) in all populations studied. LD was more fragmented across PARKIN locus in all populations. The haplotype diversity and the fragmented LD across PARKIN gene in all populations of the present study suggest the existence of frequent recombination within the large introns of the PARKIN gene.
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ABSTRACT: NOD-like receptor proteins (NLRPs) are emerging key players in several inflammatory pathways in Mammals. The first identified gene coding for a protein from this family is Nlrp5 and was originally called Mater for "Maternal Antigen That Mouse Embryos Require" for normal development beyond the two-cell stage. This important discovery was followed by the identification of other NLRPs playing roles in inflammatory disorders and of the first maternal-effect gene in humans, NLRP7, which is responsible for an aberrant form of human pregnancy called hydatidiform mole (HM). In this review, we recapitulate the various aspects of the pathology of HM, highlight recent advances regarding NLRP7 and its role in HM and related forms of reproductive losses, and expand our discussion to other NLRPs with a special emphasis on those with known roles in mammalian reproduction. Our aim is to facilitate the genetic complexity of recurrent fetal loss in humans and encourage interdisciplinary collaborations in the fields of NLRPs and reproductive loss.Frontiers in Immunology 01/2013; 4:242. DOI:10.3389/fimmu.2013.00242