Alternative titles; symbols
HGNC Approved Gene Symbol: TBC1D4
Cytogenetic location: 13q22.2 Genomic coordinates (GRCh38): 13:75,283,503-75,482,169 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q22.2 | {Diabetes mellitus, noninsulin-dependent, 5} | 616087 | 3 |
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1998) cloned TBC1D4, which they designated KIAA0603. The deduced 1,299-amino acid protein shares significant similarity with mouse Tbc1 (TBC1D1; 609850), suggesting a role in cell signaling and communication. RT-PCR analysis detected TBC1D4 expression in all tissues examined, with highest levels in kidney, skeletal muscle, ovary, and heart.
Matsumoto et al. (2004) reported that the TBC1D4 protein contains 2 N-terminal phosphotyrosine interaction domains and a C-terminal TBC domain. The region containing the TBC domain shares 31% homology with human RAB GTPase-activating protein-1 (RABGAP1; 615882). A C-terminal region containing most of the TBC domain of TBC1D4 was predicted to have a tertiary structure similar to the GTPase-activating site structure of yeast Gyp1, suggesting that arg973 is essential to the GTPase-activating site of TBC1D4. Northern blot analysis detected a 6-kb transcript in several tissues, with highest expression in heart and skeletal muscle. A 5-kb transcript was also observed in placenta and several immune tissues, including spleen, lymph node, and leukocyte.
Using Northern blot analysis, Kurihara et al. (2002) showed that mouse Tbc1d4 was expressed at low levels at embryonic days 7 and 11, but that expression increased at embryonic days 15 and 17. In adult mice, Tbc1d4 was detected at variable levels in all tissues examined, with highest expression in heart.
Kurihara et al. (2002) determined that the 5-prime ends of the mouse and human TBC1D4 genes contain a conserved CpG island.
By radiation hybrid analysis, Nagase et al. (1998) mapped the TBC1D4 gene to chromosome 13. By genomic sequence analysis, Kurihara et al. (2002) mapped the TBC1D4 gene to chromosome 13q22. They mapped the mouse Tbc1d4 gene to a syntenic region of chromosome 14.
Using differential display analysis and RT-PCR, Matsumoto et al. (2004) found that TBC1D4 was upregulated in peripheral blood CD3 (see 186740)-positive cells from atopic dermatitis (AD; see 603165) patients compared with normal control cells. Expression was highest in CD3-positive cells from patients with moderate pathology. Among leukocyte subsets from 5 healthy subjects, TBC1D4 expression was highest in T cells, particularly CD4 (186940)-positive/CD45RO (151460)-positive memory T cells. TBC1D4 expression was transiently upregulated following in vitro stimulation of T cells with anti-CD3 antibodies or calcium mobilization.
In muscle and fat cells, insulin (INS; 176730) stimulation activates a signaling cascade that causes intracellular vesicles containing glucose transporter-4 (GLUT4, or SLC2A4; 138190) to translocate to and fuse with the plasma membrane. Using mass spectrometry, Larance et al. (2005) identified AS160, insulin-regulated aminopeptidase (IRAP, or LNPEP; 151300), Rab10 (612672), Rab11 (see RAB11A; 605570), and Rab14 (612673) on Glut4 vesicles from cultured mouse adipocytes. Association of As160 with Glut4 vesicles was mediated in part by direct interaction with the cytosolic tail of membrane-bound Irap. The As160-Irap interaction was insulin dependent, and As160 dissociated from Glut4 vesicles with insulin exposure. Knockdown of As160 expression via small interfering RNA led to increased levels of Glut4 at the plasma membrane in the basal state.
Miinea et al. (2005) stated that phosphorylation of AS160 in adipocytes by AKT (see AKT1; 164730) is required for insulin-stimulated translocation of GLUT4 to the plasma membrane. They found that the purified recombinant GTPase-activating protein (GAP) domain of human AS160 showed GAP activity with RAB2A (RAB2; 179509), RAB8A (165040), RAB10, and RAB14, but not with 14 other RABs. Immunoblot analysis showed that these RABs associated with Glut4-positive vesicles in mouse adipocytes. Mutation of arg673 to leu inactivated AS160. Miinea et al. (2005) concluded that AK160 functions as a RAB GAP and that RABs may participate in GLUT4 translocation.
Karlsson et al. (2005) found that expression of AS160 protein was similar in muscle biopsy samples from 9 control subjects and from 10 patients with type-2 diabetes (125853). However, phosphorylation of AS160 in response to physiologic hyperinsulinemia was reduced 39% (p less than 0.05) in diabetic samples compared with controls. Impaired AS160 phosphorylation with diabetes was related to aberrant AKT signaling. Phosphorylation on thr308 of AKT was impaired 51% (p less than 0.05) in type-2 diabetic samples compared with controls, whereas phosphorylation on ser473 of AKT was not significantly reduced. Karlsson et al. (2005) concluded that physiologic hyperinsulinemia increases AS160 phosphorylation in normal human skeletal muscle, and they suggested that defects in insulin action on AS160 may impair GLUT4 trafficking in type 2 diabetes.
Bouzakri et al. (2008) found that human and mouse pancreatic beta cells expressed AS160 and that AS160 was phosphorylated after glucose stimulation. AS160 mRNA expression was downregulated in pancreatic islets from individuals with type-2 diabetes. In mouse insulin-secreting cells, glucose induced phosphorylation of Akt and As160, and this was mediated by insulin receptor (INSR; 147670), Irs2 (600797), and PI3 kinase (see 601232) independently of changes in cytosolic Ca(2+). Knockdown of AS160 in mouse cells increased basal insulin secretion, but it abolished glucose-stimulated insulin release. As160 knockdown also increased apoptosis and loss of glucose-induced proliferation. Bouzakri et al. (2008) concluded that AS160 is a major effector of insulin signaling in pancreatic beta cells.
Type 2 Diabetes, Susceptibility to
In an association mapping study of type 2 diabetes (T2D)-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes, followed by array-based genotyping and exome sequencing, Moltke et al. (2014) discovered a nonsense mutation (R684X; 612465.0002) in the TBC1D4 gene with an allele frequency of 17%. This variant was strongly associated with T2D and elevated circulating glucose and insulin levels after an oral glucose load (T2D5; 616087). The effect sizes of the variant markedly exceeded previously reported associations of common genetic variants with metabolic traits. The R684X variant leads to a prematurely terminated transcript of the long isoform of TBC1D4, which in homozygous carriers causes insulin resistance in skeletal muscle and confers a high risk of a subtype of T2D that is characterized by a deterioration of postprandial glucose homeostasis.
Acanthosis Nigricans and Insulin Resistance
For discussion of a mutation in the TBC1D4 gene as a possible cause of acanthosis nigricans and insulin resistance, see 612465.0001.
This variant is classified as a variant of unknown significance because its contribution to acanthosis nigricans and insulin resistance (see 610549) has not been confirmed.
In 2 half sisters with acanthosis nigricans and extreme postprandial hyperinsulinemia, Dash et al. (2009) identified heterozygosity for a c.1087C-T transition in exon 3 of TBC1D4, resulting in an arg363-to-ter (R363X) substitution predicted to cause loss of a putative GAP domain and several AKT phosphorylation sites. The mutation was present in their mother and a maternal aunt, neither of whom exhibited acanthosis nigricans but who did have a disproportionate rise in insulin following oral glucose load. Their maternal grandmother, who also carried the mutation, showed a normal peak-to-fasting insulin ratio but had elevated fasting glucose and impaired glucose tolerance, indicative of significant beta-cell dysfunction. The mutation was not found in an unaffected aunt who was obese but had normal glucose tolerance and a normal peak-to-fasting insulin ratio, or in 200 ethnically matched alleles. Functional analysis in 3T3-L1 adipocytes demonstrated that the mutation significantly reduced insulin-stimulated GLUT4 (138190) cell membrane translocation. When coexpressed with wildtype TBC1D4, the mutant dimerized with wildtype protein, suggesting that the heterozygous truncated variant might interfere with its wildtype counterpart in a dominant-negative fashion. The proband was screened for mutations in 7 additional genes implicated in GLUT4 translocation, but no mutations were identified.
Moltke et al. (2014) reported a novel association of a variant in the TBC1D4 gene, a C-to-T transition in exon 11 (c.2050C-T, rs61736969) resulting in an arg684-to-ter substitution (R684X), with type 2 diabetes and elevated circulating glucose and insulin levels after an oral glucose load (T2D5; 616087). The authors showed that homozygous carriers of this variant from the Inuit Health in Transition (IHIT) cohort had markedly higher concentrations of plasma glucose (beta = 3.8 mmol/l, p = 2.5 x 10(-35)) and serum insulin (beta = 165 pmol/l, p = 1.5 x 10(-20)) 2 hours after an oral glucose load compared with both noncarriers and heterozygous carriers. Furthermore, homozygous carriers had marginally lower concentrations of fasting plasma glucose (beta = -0.18 mmol/l, p = 1.1 x 10(-6)) and fasting serum insulin (beta = 8.3 pmol/l, p = 0.0014), and their T2D risk was markedly increased (OR = 10.3, p = 1.6 x 10(-24)). Heterozygous carriers had a moderately higher plasma glucose concentration 2 hours after an oral glucose load than noncarriers (beta = 0.43 mmol/l, p = 5.3 x 10(-5)). Analyses of skeletal muscle biopsies showed lower mRNA and protein levels of the long isoform of TBC1D4 and lower muscle protein levels of GLUT4 (SLC2A4; 138190) with an increasing number of R684X alleles. These findings were concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycemia, impaired glucose tolerance, and T2D. Moltke et al. (2014) found that the R684X variant had a minor allele frequency (MAF) of 17% in the IHIT cohort. In comparison, this variant was found in 1 Japanese individual out of the 1,092 individuals sequenced in the 1000 Genomes Project, and it was not present in exome sequencing data from 2,000 Danish individuals, 448 Han Chinese, or approximately 6,500 European and African American individuals. Moltke et al. (2014) stated that the R684X variant accounts for more than 10% of all cases of T2D in Greenland.
Bouzakri, K., Ribaux, P., Tomas, A., Parnaud, G., Rickenbach, K., Halban, P. A. Rab GTPase-activating protein AS160 is a major downstream effector of protein kinase B/Akt signaling in pancreatic beta-cells. Diabetes 57: 1195-1204, 2008. [PubMed: 18276765] [Full Text: https://doi.org/10.2337/db07-1469]
Dash, S., Sano, H., Rochford, J. J., Semple, R. K., Yeo, G., Hyden, C. S. S., Soos, M. A., Clark, J., Rodin, A., Langenberg, C., Druet, C., Fawcett, K. A., Tung, Y. C. L., Wareham, N. J., Barroso, I., Lienhard, G. E., O'Rahilly, S., Savage, D. B. A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proc. Nat. Acad. Sci. 106: 9350-9355, 2009. [PubMed: 19470471] [Full Text: https://doi.org/10.1073/pnas.0900909106]
Karlsson, H. K. R., Zierath, J. R., Kane, S., Krook, A., Lienhard, G. E., Wallberg-Henriksson, H. Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes 54: 1692-1697, 2005. [PubMed: 15919790] [Full Text: https://doi.org/10.2337/diabetes.54.6.1692]
Kurihara, L. J., Semenova, E., Miller, W., Ingram, R. S., Guan, X.-J., Tilghman, S. M. Candidate genes required for embryonic development: a comparative analysis of distal mouse chromosome 14 and human chromosome 13q22. Genomics 79: 154-161, 2002. [PubMed: 11829485] [Full Text: https://doi.org/10.1006/geno.2002.6692]
Larance, M., Ramm, G., Stockli, J., van Dam, E. M., Winata, S., Wasinger, V., Simpson, F., Graham, M., Junutula, J. R., Guilhaus, M., James, D. E. Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. J. Biol. Chem. 280: 37803-37813, 2005. [PubMed: 16154996] [Full Text: https://doi.org/10.1074/jbc.M503897200]
Matsumoto, Y., Imai, Y., Yoshida, N. L., Sugita, Y., Tanaka, T., Tsujimoto, G., Saito, H., Oshida, T. Upregulation of the transcript level of GTPase activating protein KIAA0603 in T cells from patients with atopic dermatitis. FEBS Lett. 572: 135-140, 2004. [PubMed: 15304337] [Full Text: https://doi.org/10.1016/j.febslet.2004.07.023]
Miinea, C. P., Sano, H., Kane, S., Sano, E., Fukuda, M., Peranen, J., Lane, W. S., Lienhard, G. E. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem. J. 391: 87-93, 2005. [PubMed: 15971998] [Full Text: https://doi.org/10.1042/BJ20050887]
Moltke, I., Grarup, N., Jorgensen, M. E., Bjerregaard, P., Treebak, J. T., Fumagalli, M., Korneliussen, T. S., Andersen, M. A., Nielsen, T. S., Krarup, N. T., Gjesing, A. P., Zierath, J. R., and 11 others. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature 512: 190-193, 2014. [PubMed: 25043022] [Full Text: https://doi.org/10.1038/nature13425]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]