A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of juvenile Parkinsonism in a population from North West Colombia

Pineda-Trujillo, Nicolás; Carvajal‐Carmona, Luis G.; Buriticá, Omar; Moreno, Sonia; Uribe, Carlos Santiago; Piñeda, David; Toro, María Eugenia; Garcı́a, Francisco; Arias, William; Bedoya, Gabriel; Lopera, Francisco; Ruiz-Linares, Andrés

doi:10.1016/s0304-3940(00)01733-x

Cited by 52 publications

(41 citation statements)

References 16 publications

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“…Furthermore, based on our present findings, we propose that a combined therapy with antioxidant and high energetic agents should provide to pre-clinical genetically individuals at risk to suffer PD a means to delay or to prevent motor symptoms and/or frank PD-ARJP disorders, as those encounter in Antioquia, Colombia (Pineda-Trujillo et al, 2001, 2009. These data may contribute to a better understanding of the inherent nutritional status, genetic predisposition and environmental agents as causative factors of PD.…”

Section: Resultssupporting

confidence: 53%

Human Lymphocytes and Drosophila melanogaster as Model System to Study Oxidative Stress in Parkinson's Disease

Jiménez-Del-Río¹,

Vélez-Pardo²

2012

Mechanisms in Parkinson's Disease - Models and Treatments

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Section: Resultssupporting

confidence: 53%

Human Lymphocytes and Drosophila melanogaster as Model System to Study Oxidative Stress in Parkinson's Disease

Jiménez-Del-Río¹,

Vélez-Pardo²

2012

Mechanisms in Parkinson's Disease - Models and Treatments

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Section: Autosomal Recessive Juvenile Parkinson Disease (Arjp)mentioning

confidence: 99%

“…The hereditary nature of ARJP implicates a number of mutations in the genes encoding the proteins parkin, PINK1, LRRK2, and DJ-1 as the cause of dopaminergic neurodegeneration (1-4). A variety of deletion, truncation, and point mutations distributed throughout the park2 gene, which encodes the protein parkin, have been reported in ARJP patients (1,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).Parkin functions as a ubiquitin ligase (E3) and belongs to a family of RBR (RING-between-RING) ubiquitin ligase enzymes involved in proteosome-mediated protein degradation (19 -21). The currently accepted domain architecture of parkin, deduced from multiple sequence alignment, shows that the C terminus of the protein is characterized by two ϳ50-residue RING (really interesting new gene) domains separated by a 51-residue IBR (In-Between-RING) domain (22,23).…”

mentioning

confidence: 99%

Identification of a Novel Zn2+-binding Domain in the Autosomal Recessive Juvenile Parkinson-related E3 Ligase Parkin

Hristova¹,

Beasley²,

Rylett

et al. 2009

Journal of Biological Chemistry

123

119

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Missense mutations in park2, encoding the parkin protein, account for ϳ50% of autosomal recessive juvenile Parkinson disease (ARJP) cases. Parkin belongs to the family of RBR (RING-between-RING) E3 ligases involved in the ubiquitin-mediated degradation and trafficking of proteins such as Pael-R and synphillin-1. The proposed architecture of parkin, based largely on sequence similarity studies, consists of N-terminal ubiquitin-like and C-terminal RBR domains. These domains are separated by a ϳ160-residue unique parkin sequence having no recognizable domain structure. We used limited proteolysis experiments on bacterially expressed and purified parkin to identify a new domain (RING0) within the unique parkin domain sequence. RING0 comprises two distinct, conserved cysteine-rich clusters between Cys 150 -Cys 169 and Cys 196 -His 215 consisting of CX 2 -3 CX 11 CX 2 C and CX 4 -6 CX 10 -16 -CX 2 (H/C) motifs. The positions of the cysteine/histidine residues in this region bear similarity to parkin RING1 and RING2 domains, as well as other E3 ligase RING domains. However, in parkin a 26-residue linker region separates the motifs, which is not typical of other RING domain structures. Further, the RING0 domain includes all but one of the known ARJP mutation sites between the ubiquitin-like and RBR regions of parkin. Using electrospray ionization mass spectrometry and inductively coupled plasma-atomic emission spectrometry analysis, we determined that the RING0, RING1, IBR, and RING2 domains each bind two Zn 2؉ ions, the first observation of an E3 ligase with the ability to bind eight metal ions. Removal of the zinc from parkin causes near complete unfolding of the protein, an observation that rationalizes cysteine-based ARJP mutations found throughout parkin, including RING0 (C212Y) that form cellular inclusions and/or are defective for ubiquitination likely because of poor zinc binding and misfolding. The identification of the RING0 domain in parkin provides a new overall domain structure for the protein that will be important in assessing the roles of ARJP mutations and designing experiments aimed at understanding the disease. Autosomal recessive juvenile Parkinson disease (ARJP)2 is a neurodegenerative disorder arising from the loss of dopaminergic neurons in the substantia nigra of the midbrain. ARJP is characterized by the onset of Parkinsonian symptoms such as tremors, rigidity, and bradykinesia. It is distinguished from the idiopathic form of Parkinson disease by the onset of symptoms, prior to the age of forty. The hereditary nature of ARJP implicates a number of mutations in the genes encoding the proteins parkin, PINK1, LRRK2, and DJ-1 as the cause of dopaminergic neurodegeneration (1-4). A variety of deletion, truncation, and point mutations distributed throughout the park2 gene, which encodes the protein parkin, have been reported in ARJP patients (1,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).Parkin functions as a ubiquitin ligase (E3) and belongs to a family of RBR (RING-between-RING) ubiquitin li...

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“…A more detailed description of the Paisas has been published elsewhere. [41][42][43][44][45] Racial admixture estimations, 43 evolutionary reconstruction using phylogenetic methods, 44,46 genotyping of specific chromosomal Y and mitochondrial markers 46 and the presence of strong founder effects for some deleterious mutations resulting in neurodegenerative diseases, such as Early Onset Alzheimer Disease (PS-1 E280A), CADASIL (notch3 C455R) and Parkinson Disease (Parkin Cys212Tyr), [47][48][49][50][51][52] all support the conclusion that this community exhibits the features of a genetic isolate.…”

Section: Sample Ascertainment and Clinical Diagnosismentioning

confidence: 99%

Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate

et al. 2004

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Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attentiondeficit/hyperactivity disorder (ADHD) has been suggested by case-control-and nuclear-familybased studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/ linkage. Two-point LOD scores were significantly negative, with values ranging from À3.21 (P ¼ 0.011158) to À7.66 (P ¼ 0.000091 at h ¼ 0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P ¼ 0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P ¼ 0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele.

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A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of juvenile Parkinsonism in a population from North West Colombia

Cited by 52 publications

References 16 publications

Human Lymphocytes and Drosophila melanogaster as Model System to Study Oxidative Stress in Parkinson's Disease

Human Lymphocytes and Drosophila melanogaster as Model System to Study Oxidative Stress in Parkinson's Disease

Identification of a Novel Zn2+-binding Domain in the Autosomal Recessive Juvenile Parkinson-related E3 Ligase Parkin

Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate

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