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HGNC Approved Gene Symbol: RRAD
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:66,921,685-66,925,535 (from NCBI)
To identify the gene or genes associated with insulin resistance in type 2 (noninsulin-dependent) diabetes mellitus (T2D; 125853), Reynet and Kahn (1993) prepared subtraction libraries from skeletal muscle of normal and diabetic humans, screened with subtracted probes, and identified RRAD, which they called RAD (RAS associated with diabetes), as selectively overexpressed in type 2 diabetic muscle as compared to muscle of nondiabetic or type 1 diabetic individuals. RRAD encodes a novel 29-kD member of the Ras-guanosine triphosphatase superfamily. RRAD mRNA was expressed primarily in skeletal and cardiac muscle and was increased an average of 8.6-fold in the muscle of type 2 diabetics as compared with normal individuals. Southern blot analysis of the RRAD gene did not reveal any evidence of gene amplification or rearrangement; a detailed analysis of the RRAD promoter was required to determine if some regulatory element played a role in the overexpression of the gene in type 2 diabetes.
Doria et al. (1995) used linkage analysis to map the RRAD gene to a 3-cM region on chromosome 16q defined by the markers D16S265, D16S186, and D16S397 (lod scores = 10.08, 10.9, and 10.84, respectively; theta = 0.024, 0.001, and 0.03, respectively). By fluorescence in situ hybridization, they mapped the RRAD gene to chromosome 16q22.
Liu et al. (2020) identified the mechanism by which beta-adrenergic agonists stimulate voltage-gated calcium channels. Liu et al. (2020) expressed alpha-1C or beta-2B subunits conjugated to ascorbate peroxidase in mouse hearts, and used multiplexed quantitative proteomics to track hundreds of proteins in the proximity of CaV1.2 (CACNA1C; 114205). They observed that the calcium-channel inhibitor Rad is enriched in the CaV1.2 microenvironment but is depleted during beta-adrenergic stimulation. Phosphorylation by protein kinase A (see 176911) of specific serine residues on Rad decreases its affinity for beta subunits and relieves constitutive inhibition of CaV1.2, observed as an increase in channel open probability. Expression of Rad or its homolog Rem (610388) in HEK293T cells also imparted stimulation of CaV1.3 (CACNA1D; 114206) and CaV2.2 (CACNA1B; 601012) by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.
Doria et al. (1995) identified a trinucleotide repeat polymorphism, referred to as RAD1, in the RRAD gene. They reported that the frequency distribution of RAD1 alleles was different between white American T2D patients and control subjects. When the allele distribution was analyzed by structural classes of the (GTT)n(ATT)n polymorphism, it was found that all the alleles associated with T2D belonged to molecular classes I, II, and IV but not to class III. In comparison with class III homozygotes, carriers of alleles in any of the other 3 classes had a relative risk of 2.9 for T2D. The authors proposed that T2D-associated RAD1 alleles or some other sequence differences in linkage disequilibrium with them could be located inside positive or negative cis-acting elements regulating the transcription of RAD1. Doria et al. (1995) also speculated that overexpression of RAD in T2D muscle could be the result of allelic variability in the interaction between the polymorphic RAD1 sequence and transcription factors.
In an attempt to replicate the finding that the trinucleotide repeat polymorphism RAD1 of the RRAD gene is associated with T2D, Orho et al. (1996) screened RAD1 and another microsatellite marker at the D16S265 loci, which is located near the RRAD locus, with a radioactive PCR method in 290 unrelated Finnish NIDDM patients and 270 control subjects and related the findings to measures of insulin sensitivity. Both groups were randomly selected from the western and southern parts of Finland. Orho et al. (1996) found that the allele frequency distributions of RAD1 and D16S265 did not differ between T2D patients and control subjects.
Ilany et al. (2006) generated mice overexpressing Rad in muscle and observed normal growth, glucose tolerance, and insulin sensitivity, but reduced plasma triglyceride levels. On a high-fat diet, the transgenic mice developed more severe glucose intolerance than wildtype mice due to increased insulin resistance in muscle, and there was a further reduction in plasma triglyceride levels associated with increased levels of lipoprotein lipase (609708) in the transgenic mice. Ilany et al. (2006) concluded that there is a potential synergistic interaction between increased expression of RAD and high-fat diet in the creation of insulin resistance and the altered lipid metabolism present in type 2 diabetes.
Doria, A., Caldwell, J. S., Ji, L., Reynet, C., Rich, S. S., Weremowicz, S., Morton, C. C., Warram, J. H., Kahn, C. R., Krolewski, A. S. Trinucleotide repeats at the rad locus: allele distributions in NIDDM and mapping to a 3-cM region on chromosome 16q. Diabetes 44: 243-247, 1995. [PubMed: 7859947] [Full Text: https://doi.org/10.2337/diab.44.2.243]
Ilany, J., Bilan, P. J., Kapur, S., Caldwell, J. S., Patti, M.-E., Marette, A., Kahn, C. R. Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level. Proc. Nat. Acad. Sci. 103: 4481-4486, 2006. [PubMed: 16537411] [Full Text: https://doi.org/10.1073/pnas.0511246103]
Liu, G., Papa, A., Katchman, A. N., Zakharov, S. I., Roybal, D., Hennessey, J. A., Kushner, J., Yang, L., Chen, B.-X., Kushnir, A., Dangas, K., Gygi, S. P., Pitt, G. S., Colecraft, H. M., Ben-Johny, M., Kalocsay, M., Marx, S. O. Mechanism of adrenergic Ca(V)1.2 stimulation revealed by proximity proteomics. Nature 577: 695-700, 2020. [PubMed: 31969708] [Full Text: https://doi.org/10.1038/s41586-020-1947-z]
Orho, M., Carlsson, M., Kanninen, T., Groop, L. C. Polymorphism at the rad gene is not associated with NIDDM in Finns. Diabetes 45: 429-433, 1996. [PubMed: 8603763] [Full Text: https://doi.org/10.2337/diab.45.4.429]
Reynet, C., Kahn, C. R. Rad: a member of the Ras family overexpressed in muscle of type II diabetic humans. Science 262: 1441-1444, 1993. [PubMed: 8248782] [Full Text: https://doi.org/10.1126/science.8248782]