Genetic variability at the PARK16 locus

Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
European journal of human genetics: EJHG (Impact Factor: 4.35). 12/2010; 18(12):1356-9. DOI: 10.1038/ejhg.2010.125
Source: PubMed


Parkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of loss of dopaminergic neurons in the substantia nigra and intracytoplasmic neuronal inclusions containing alpha-synuclein aggregations known as Lewy bodies. Although the majority of PD is idiopathic, pathogenic mutations in several mendelian genes have been successfully identified through linkage analyses. To identify susceptibility loci for idiopathic PD, several genome-wide association studies (GWAS) within different populations have recently been conducted in both idiopathic and familial forms of PD. These analyses have confirmed SNCA and MAPT as loci harboring PD susceptibility. In addition, the GWAS identified several other genetic loci suggestively associated with the risk of PD; among these, only one was replicated by two different studies of European and Asian ancestries. Hence, we investigated this novel locus known as PARK16 for coding mutations in a large series of idiopathic pathologically proven PD cases, and also conducted an association study in a case-control cohort from the United Kingdom. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (P-value=0.0325) was identified. Two novel coding variants present only in the PD cohort were also identified within the RAB7L1 (p.K157R) and SLC41A1 (p.A350V) genes. No copy number variation analyses have yet been performed within this recently identified locus. We concluded that, although both coding variants and risk alleles within the PARK16 locus seem to be rare, further molecular analyses within the PARK16 locus and within different populations are required in order to examine its biochemical role in the disease process.

Download full-text


Available from: Coro Paisán-Ruiz
  • Source
    • "For example, Rab7L1 regulates the intraneuronal sorting of LRRK2 and also Rab7L1 gene is located in a locus harboring PD susceptibility [67] [68]. Reduced neurite extension in cultured neurons harboring mutant LRRK2 can be rescued by overexpression of Rab7L1 supporting the idea that proper sorting is critical to its function [67]. 14-3-3 proteins may act in a similar fashion to regulate intracellular LRRK2 protein localization. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. Here, we review the evidence that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective roles against neurodegeneration.
    Full-text · Article · Dec 2013
  • Source
    • "Recently, in one PD patient, Tucci and colleagues [23] have found a coding variant of SLC41A1, carrying substitution p.A350V. Here, we have investigated if this potentially PD-associated mutation affects the molecular and/or functional properties of SLC41A1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a complex multifactorial ailment predetermined by the interplay of various environmental and genetic factors. Systemic and intracellular magnesium (Mg) deficiency has long been suspected to contribute to the development and progress of PD and other neurodegenerative diseases. However, the molecular background is unknown. Interestingly, gene SLC41A1 located in the novel PD locus PARK16 has recently been identified as being a Na(+)/Mg(2+) exchanger (NME, Mg(2+) efflux system), a key component of cellular magnesium homeostasis. Here, we demonstrate that the substitution p.A350V potentially associated with PD is a gain-of-function mutation that enhances a core function of SLC41A1, namely Na(+)-dependent Mg(2+) efflux by 69±10% under our experimental conditions (10-minute incubation in high-Na(+) (145 mM) and completely Mg(2+)-free medium). The increased efflux capacity is accompanied by an insensitivity of mutant NME to cAMP stimulation suggesting disturbed hormonal regulation and leads to a reduced proliferation rate in p.A350V compared with wt cells. We hypothesize that enhanced Mg(2+)-efflux conducted by SLC41A1 variant p.A350V might result, in the long-term, in chronic intracellular Mg(2+)-deficiency, a condition that is found in various brain regions of PD patients and that exacerbates processes triggering neuronal damage.
    Full-text · Article · Aug 2013 · PLoS ONE
  • Source
    • "In recent years, genome-wide association studies (GWAS) have identified a number of new susceptibility loci associated with PD in different ethnic groups. Of these loci, the most striking locus is PARK16, which is located in 1q23 and contains 5 genes (SLC45A3, NUCKS1, RAB7L1, SLC41A1, and PM20D1) [19]. SLC41A1 encodes a 56 kDa Mg2+ transporter consisting of 513 amino acids, it has been proposed that PD might be associated with lack of Ca2+ and Mg2+ in the brain [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The cause of almost all cases of Parkinson’s disease (PD) remains unknown. Recent years have seen an explosion in the rate of discovery of genetic defects linked to PD. Different racial and geographical populations may have different distributions of genetic variants. Methods In the current study, we screened the following genetic variants, including some rare mutations and single nucleotide polymorphisms (SNPs), in a pedigree and cases-controls. To best of our knowledge, we first screened these variants known to be associated with neurodegeneration disease, E46K (rs104893875) in SNCA, A1442P in LRRK2, IVS9 in PARK2, A350V in SLC41A1, P268S (rs2066842), R702W (rs2066844), G908R (rs2066845), 1007fs (rs2066847) in NOD2 and G2385R (rs34778348) in LRRK2 from southern China population. Genotyping was performed by jointly using primers overlapping polymerase chain reaction (PCR) site-directed mutagenesis, restriction fragment length polymorphism (RFLP), and capillary electrophoresis (CE). Results We didn’t discover above 9 variants in the family members of the pedigree. Furthermore, of 237 patients with sporadic Parkinson’s disease and 190 controls, no heterozygosity or homozygosity were found from E46K, A1442P, A350V, R702W, G908R, or 1007fs but heterozygosity onto G2385R, IVS9, and P268S. No significant difference between cases and controls was found in both allele frequency (P = 0.572) and genotype frequency (P = 0.348) of IVS9. However, significant differences in genotype frequency (P = 0.009) of G2385R were consistent with prior observation. Eight patients with Parkinson’s disease (2 women and 6 men are over the age of 50 years at onset of PD) carried the P268S heterozygous variation in NOD2. There was no heterozygosity or homozygosity of P268S in the controls. Genotype frequency of P268S (P = 0.0450) had significant differences. Conclusions Our results suggested that the P268S variant in NOD2 might be a risk factor for susceptibility to sporadic Parkinson’s disease in Chinese populations. It also implied that the inflammatory response may play a role in PD.
    Full-text · Article · May 2013 · Behavioral and Brain Functions
Show more