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Comment |
Rab5 isoforms differentially regulate the trafficking and degradation of epidermal growth factor receptors. Chen PI 2009 et al.
Ligand-mediated endocytosis is an intricate regulatory mechanism for epidermal growth factor receptor (EGFR) signal transduction. Coordinated trafficking of EGFR ensures its temporal and spatial communication with downstream signaling effectors. We focused our work on Rab5, a monomeric GTPase shown to participate in early stages of the endocytic pathway. Rab5 has three isoforms (A, B, and C) sharing more than 90% of sequence identity. We individually ablated endogenous isoforms in HeLa cells with short interfering RNAs and examined the loss-of-function phenotypes. We found that suppression of Rab5A or 5B hampered the degradation of EGFR, whereas Rab5C depletion had very little effect. The differential delay of EGFR degradation also corresponds with retarded progression of EGFR from early to late endosomes. We investigated the activators/effectors of Rab5A that can potentially separate its potency in EGFR degradation from other isoforms and found that Rin1, a Rab5 exchange factor, preferably associated with Rab5A. Moreover, Rab5A activation is sensitive to EGF stimulation, and suppression of Rin1 diminished this sensitivity. Based on our results together with previous work showing that Rin1 interacts with signal transducing adapter molecule to facilitate the degradation of EGFR (Kong, C., Su, X., Chen, P. I., and Stahl, P. D. (2007) J. Biol. Chem. 282, 15294-15301), we hypothesize that the selective association of Rab5A and Rin1 contributes to the dominance of Rab5A in EGFR trafficking, whereas the other isoforms may have major functions unrelated to the EGFR degradation pathway.
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Mutations |
3 mutations
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Shi Y et al. Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 ?10(-8): 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS.
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity. Jones MR et al. (2015) Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.//////////////////
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Association of single nucleotide polymorphisms in the RAB5B gene 3'UTR region with polycystic ovary syndrome in Chinese Han women. Yu J et al. (2019) Previous genome-wide sequencing revealed that Ras-related protein Rab-5B (RAB5B) is a susceptible target in patients with polycystic ovary syndrome (PCOS). Direct sequencing was performed to analyze the RAB5B gene rs1045435, rs11550558, rs34962186, rs705700, rs58717357, rs11171718, rs60028217, rs772920 loci genotypes in 300 PCOS patients and 300 healthy controls. The plasma microRNA (miRNA)-24, miR-320 levels were measured by reverse transcription fluorescent quantitative PCR (RT-qPCR). The risk of PCOS in C allele carriers of RAB5B gene rs1045435 locus was 3.91 times higher than that of G allele. The risk of PCOS in rs11550558 locus G allele was 4.09 times higher than A allele. The risk of PCOS in rs705700 locus C allele was 1.66 times greater than T allele. The risk of PCOS in rs11171718 locus A allele carrier was 3.84 times higher than G allele. The s11550558 SNP was associated with PCOS risk only in those with age≥31.1 years. And RAB5B gene rs11550558, rs1045435, and rs11171718 SNPs were significantly associated with PCOS risk only in subjects with BMI≥23.8kg/m2 We also found that the RAB5B gene rs1045435 SNP was associated with plasma miR-24 levels. The RAB5B gene rs11550558, rs705700, rs11171718 SNPs were correlated with plasma miR-230 levels. The single nucleotide polymorphisms of the rs1045435, rs11550558, rs705700, and rs11171718 loci of the RAB5B gene are associated with PCOS risk. The rs1045435 locus is likely a miR-24 binding site, while rs11550558, rs705700, and rs11171718 loci may be miR-320 binding sites.//////////////////
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