The association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complications

Say, Yee‐How

doi:10.1186/s40101-017-0142-x

Cited by 22 publications

(21 citation statements)

References 267 publications

(301 reference statements)

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“…In genome-wide association studies (GWAS), a significant association of DOCK5 with childhood and adult severe obesity has been reported [11,23]. The metabolic phenotype and mechanism of how DOCK5 may contribute to obesity are currently unknown.…”

Section: Discussionmentioning

confidence: 99%

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

et al. 2019

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The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high-fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5-deficient hepatocytes. Importantly, in liver-specific Raptor knockout mice and associated hepatocytes, the effects of an adeno-associated virus (AAV8)-or adenovirus-mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5-Raptor interaction is indispensable for the DOCK5-mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.

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Section: Discussionmentioning

confidence: 99%

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

et al. 2019

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“…And DOCK1 was the founding member of the DOCK family, which was widely reported to be involved in cancer survival, migration and invasion (44–46). Though DOCK5 possessed the greatest similarity to DOCK1, it was one of the least studied members in the DOCK family, and DOCK5 was associated with mast cell degranulation (47), neutrophils and osteoclasts activity (48–51), obesity (52,53) and epithelial invasion (54,55). With regard to cancer, the role of DOCK5 has been poorly understood thus far.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant

Liu

Guo

et al. 2018

Clinical Cancer Research

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2 TRANSLATIONAL RELEVANCEHPV negative HNSCC represents a distinct clinical entity from HPV positive HNSCC. Recently, alternative splicing has been shown to be closely related to tumor progression. However, the characterization of alternative splicing in HPV negative HNSCC is still largely undescribed. In this study, we identified 580 significant splicing events in HPV negative HNSCC and we identified a novel DOCK5 variant highly expressed in a separate primary tumor validation set using qRT-PCR. We demonstrated that the DOCK5 variant played an oncogenic role in HPV negative HNSCC, which could promote proliferation, migration and invasion in HPV negative HNSCC cell lines, and patients with higher expression of DOCK5 variant showed decreased overall survival. Identification of alternative splicing in HPV negative HNSCC allows for a promising avenue to identify novel therapeutic targets and expands the understanding of HNSCC carcinogenesis. KEY WORDSHead and neck squamous cell carcinoma, alternative splicing, HPV negative, DOCK5Research. Experimental Design: RNA sequencing data of 407 HPV negative HNSCC and 38 normal samples were obtained from The Cancer Genome Atlas (TCGA) and splice junctions were discovered using MapSplice.Outlier analysis was used to identify significant splicing junctions between HPV negative HNSCC and normal samples. To explore the functional role of the identified DOCK5 variant, we checked its expression with qRT-PCR in a separate primary tumor validation set and performed proliferation, migration and invasion assays.Results: 580 significant splicing events were identified in HPV negative HNSCC and the most common type of splicing events was an alternative start site (33.3%). The prevalence of a given individual ASE among the tumor cohort ranged from 9.8% and 64.4%. Within the 407 HPV negative HNSCC samples in TCGA, the number of significant ASEs differentially expressed in each tumor ranged from 17 to 290. We identified a novel candidate oncogenic DOCK5 variant confirmed using qRT-PCR in a separate primary tumor validation set. Loss-and gain-of-function experiments indicated that DOCK5 variant promoted proliferation, migration and invasion of HPV negative HNSCC cells, and patients with higher expression of DOCK5 variant showed decreased overall survival. Conclusion:Analysis of ASEs in HPV negative HNSCC identifies multiple alterations likely related to carcinogenesis, including an oncogenic DOCK5 variant.

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“…47 It is important mentioning that variant A of the GCTGT-> A INDELs generates a short mRNA that escapes the inhibition of a microRNA (a negative regulator of the expression of various mR-NAs at the post-transcriptional level), which leads to increased production of the soluble B-cell activating factor cytokine in these patients, thus causing susceptibility to the development of said diseases. 47 On the other hand, the CTTTA INDELs localized at the 3' UTR region of the LEPR gene is associated with body weight increase, 48 while the 45-bp INDELs located in the 3' UTR region of the UCP2 gene (which codes for an uncoupling protein that acts as a mitochondrial transporter and homeostasis and thermogenesis energy regulator) has been associated with body mass index and body weight alterations after food consumption. 48 Another study assessed a group of INDELs in various genes of patients with colorectal cancer; these variants in the ACE, UCP2, TYMS, IL4, NFKB1, CASP8, TP53, HLAG, UGT1A1 and SGSM3 genes were found to be associated with susceptibility and some clinical traits (Table 2).…”

Section: Indels and Multifactorial Diseasesmentioning

confidence: 99%

Role of genetic variability in Mendelian and multifactorial diseases

Ramírez‐Bello¹

2023

GMM

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VNTRs and STRs have been used in linkage studies to detect regions involved with Mendelian (or monogenic) diseases, such as Duchenne or Becker muscular dystrophy, cystic fibrosis, sickle cell anemia, etc., which due to their low prevalence are quite rare in populations. These diseases have the characteristic that a single altered gene results in a phenotype (Fig. 1), given that the mutation has great biological effect; however, there are always exceptions and, in some cases, even if a mutation occurs, it will not lead to the disease

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The association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complications

Cited by 22 publications

References 267 publications

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant

Role of genetic variability in Mendelian and multifactorial diseases

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