Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma-specific survival

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

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Association between Polymorphism rs1799732 of DRD2 Dopamine Receptor Gene and Personality Traits among MMA Athletes

Genes ◽

10.3390/genes12081217 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1217

Author(s):

Marta Niewczas ◽

Anna Grzywacz ◽

Katarzyna Leźnicka ◽

Krzysztof Chmielowiec ◽

Jolanta Chmielowiec ◽

...

Keyword(s):

High Risk ◽

Personality Traits ◽

Dopamine Receptor ◽

Martial Arts ◽

Genetic Variants ◽

Receptor Gene ◽

Harm Avoidance ◽

Novelty Seeking ◽

Genes Encoding ◽

Dopamine Receptor Gene

Four factors—namely, harm avoidance, novelty seeking, reward addiction and persistence—represent the nature of temperament that is not genetically determined in itself. It was shown in earlier studies that a strong propensity to look for novelty or a tendency to engage in risky behavior is correlated with genetic variants in the area of the genes encoding dopamine receptors. Therefore, the aim of this study is to determine whether there is a relationship between personality traits and genetic variants in the area of the DRD2 dopamine receptor gene in MMA athletes. The participants consisted of 85 mixed martial arts (MMA) athletes and 284 healthy, non-MMA male participants. Their personality traits were measured using the Revised Temperament and Character Inventory. Blood was collected for genetic assays and all samples were genotyped using the real-time PCR method. We observed a statistically significant effect of a complex factor of the DRD2 rs1799732 genotype on MMA participants’ control and reward dependence. Engaging in high-risk sport may be associated with several personality characteristics. The DRD2 rs1799732 polymorphism may be associated with reduced harm avoidance in martial arts athletes, thereby modulating athletes’ predisposition to participate in high-risk sport.

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Genetic variants of SDCCAG8 and MAGI2 in mitosis‐related pathway genes are independent predictors of cutaneous melanoma‐specific survival

Cancer Science ◽

10.1111/cas.15102 ◽

2021 ◽

Author(s):

Yuanmin He ◽

Hongliang Liu ◽

Sheng Luo ◽

Christopher I. Amos ◽

Jeffrey E. Lee ◽

...

Keyword(s):

Cutaneous Melanoma ◽

Genetic Variants ◽

Related Pathway

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Evaluation of the Influence of Genetic Variants of SLC2A9 (GLUT9) and SLC22A12 (URAT1) on the Development of Hyperuricemia and Gout

Journal of Clinical Medicine ◽

10.3390/jcm9082510 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2510

Author(s):

Katerina Pavelcova ◽

Jana Bohata ◽

Marketa Pavlikova ◽

Eliska Bubenikova ◽

Karel Pavelka ◽

...

Keyword(s):

Metabolic Syndrome ◽

Uric Acid ◽

Genetic Variants ◽

Biochemical Parameters ◽

Previous Analysis ◽

Direct Sequencing ◽

Low Frequency ◽

European Population ◽

The Body ◽

Genes Encoding

Urate transporters, which are located in the kidneys, significantly affect the level of uric acid in the body. We looked at genetic variants of genes encoding the major reabsorption proteins GLUT9 (SLC2A9) and URAT1 (SLC22A12) and their association with hyperuricemia and gout. In a cohort of 250 individuals with primary hyperuricemia and gout, we used direct sequencing to examine the SLC22A12 and SLC2A9 genes. Identified variants were evaluated in relation to clinical data, biochemical parameters, metabolic syndrome criteria, and our previous analysis of the major secretory urate transporter ABCG2. We detected seven nonsynonymous variants of SLC2A9. There were no nonsynonymous variants of SLC22A12. Eleven variants of SLC2A9 and two variants of SLC22A12 were significantly more common in our cohort than in the European population (p = 0), while variants p.V282I and c.1002+78A>G had a low frequency in our cohort (p = 0). Since the association between variants and the level of uric acid was not demonstrated, the influence of variants on the development of hyperuricemia and gout should be evaluated with caution. However, consistent with the findings of other studies, our data suggest that p.V282I and c.1002+78A>G (SLC2A9) reduce the risk of gout, while p.N82N (SLC22A12) increases the risk.

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Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics

Cells ◽

10.3390/cells9040835 ◽

2020 ◽

Vol 9 (4) ◽

pp. 835 ◽

Cited By ~ 1

Author(s):

Daji Guo ◽

Xiaoman Yang ◽

Lei Shi

Keyword(s):

Animal Models ◽

Rho Gtpases ◽

Rho Gtpase ◽

Autism Spectrum ◽

Neuronal Morphology ◽

Nucleotide Exchange ◽

Cellular Processes ◽

Research Initiative ◽

Genes Encoding ◽

And Function

The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed.

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