Translated mutation in the Nurr1 gene as a cause for Parkinson's disease

Abstract

Multiple genes have been now identified as causing Parkinson's disease (PD). In 2003, two mutations were identified in exon 1 of the Nurr1 gene in 10 of 107 individuals with familial PD. To date, investigators have only focused on screening for these known mutations of the Nurr1 gene. All individuals were recruited from two Parkinson's disease clinics in Canada. Following PCR amplification of each exon of the Nurr1 gene, samples underwent denaturing high-performance liquid chromatography (DHPLC) analysis. Ten individuals also underwent direct sequencing as well as any samples where variants were identified. The Nurr1 gene was evaluated for 202 PD individuals, 37% of whom had at least one relative with PD and 100 control non-PD individuals. Using DHPLC and direct sequencing, we did not detect any sequence variants in exon 1. Variants in amplicon 6 were seen and direct sequencing confirmed a known NI6P polymorphism in intron 6. Novel polymorphisms were also identified in exon 3 and intron 5. A novel mutation was identified in exon 3 in one nonfamilial PD individual. This heterozygous C-to-G transversion resulted in a serine-to-cysteine substitution and was not identified in any of the other 602 chromosomes screened. Mutations in the Nurr1 gene in our large cohort of familial and sporadic PD individuals are rare. The novel mutation in exon 3 is predicted to affect phosphorylation and functional studies to assess this are underway. This is the first coding mutation identified in the Nurr1 gene for Parkinson's disease.

Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons

“…Several developmental transcription factors, including Nurr1, Lmx1a/b, Engrailed 1, and Pitx3, remain expressed in mature DA neurons, and nucleotide polymorphisms in human genes encoding these factors have been associated with PD (11)(12)(13)(23)(24)(25)(26). Moreover, analysis of postmortem brain tissue has demonstrated down-regulation of Nurr1 and other key transcription factors in remaining DA neurons in PD, and significantly reduced Nurr1 and Pitx3 mRNA expression levels in peripheral blood cells in PD patients (14,15).…”

“…In Nurr1 null gene-targeted mice, DA neurons fail to differentiate, and DA neuron markers are absent at birth (7)(8)(9). Several recent studies have suggested that disrupted Nurr1 function in adult DA neurons may contribute to the cellular pathology in PD; Nurr1 gene polymorphisms have been associated with PD, and Nurr1 heterozygous mutant mice show increased vulnerability to DA neuron toxic insults (10)(11)(12)(13). Moreover, Nurr1 is down-regulated in peripheral lymphocytes of PD patients, and postmortem studies have found that in PD, Nurr1 is down-regulated in the remaining DA neurons showing signs of neuropathology (14,15).…”

Nurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine Neurons

“…Nurr1 expression is diminished in neurons with ␣-synuclein inclusions in postmortem PD brain tissue, and Nurr1 mutations and polymorphisms have been identified in rare cases of PD (Xu et al, 2002;Le et al, 2003;Zheng et al, 2003;Grimes et al, 2006). However, the significance of genetic lesions remain unclear (Wellenbrock et al, 2003;Hering et al, 2004;Tan et al, 2004).…”

Nurr1: A New Insight to Protects Dopaminergic Neurodegeneration in Parkinson’s disease

“…Mutations in NR4A2 and decrease in Nurr1-positive SN neurons have also been shown in PD cases [54,55,56] , thus further supporting a link between altered Nurr1expression and PD progression. Recently, two mutations located in exon 1 of the Nurr1 gene were reported in10 out of 107 individuals with familial PD, and resulted in a marked decrease in Nurr1 mRNA [57] .…”

“…The variants in Nurr1 in PD seem to be very rare and population-restricted [21,78,79,80] . Recently, two novel variants at exon3 of Nurr1 gene were identified in two non-familial PD patients [81] . The first, a heterozygous C→G transvertion at exon3 (253), changes the amino acid serine to cysteine and the second is a223C→T sequence.…”