Alternative titles; symbols
HGNC Approved Gene Symbol: ADCY3
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38): 2:24,819,169-24,920,237 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | {Obesity, susceptibility to, BMIQ19} | 617885 | Autosomal recessive | 3 |
ADCY3 belongs to the adenylate cyclase (EC 4.6.1.1) family of enzymes responsible for the synthesis of cAMP (Ludwig and Seuwen, 2002).
Using a PCR-based screening method with primers based on the rat ADCY3 sequence, Yang et al. (1999) cloned human ADCY3 from a fetal brain cDNA library. The deduced 1,144-amino acid protein has a calculated molecular mass of 129 kD. It contains 2 large hydrophobic regions, each consisting of 6 transmembrane-spanning domains typical of other adenylate cyclase isoforms. ADCY3 also has 6 putative N-linked glycosylation sites, a predicted protein kinase A site, 2 tyrosine kinase sites, and many potential protein kinase C sites throughout the sequence. The human and rat proteins share 95% sequence homology. By semiquantitative RT-PCR, Yang et al. (1999) found expression of ADCY3 in all tissues examined, with highest expression in lung and placenta, intermediate expression in brain, heart, kidney, and skeletal muscle, and lowest expression in liver and pancreas. Isolated pancreatic islet mRNA also showed high expression. By semiquantitative RT-PCR, Ludwig and Seuwen (2002) detected highest ADCY3 expression in placenta, testis, ovary, and colon, and weaker expression in all other tissues except skeletal muscle.
Ludwig and Seuwen (2002) determined that the ADCY3 gene contains 22 exons and spans over 100 kb.
By Southern blot analysis of somatic cell hybrid DNAs, Gaudin et al. (1994) mapped the ADCY3 gene to chromosome 2. Using isotopic in situ hybridization, Haber et al. (1994) mapped the ADCY3 gene to 2p24-p22.
By fluorescence in situ hybridization, Edelhoff et al. (1995) mapped the mouse Adcy3 gene to chromosome 12 in the A-B region.
Sinnarajah et al. (2001) reported that RGS2 (600861) reduces cAMP production by odorant-stimulated olfactory epithelium membranes, in which the alpha-S family member alpha-olf (139312) links odorant receptors to adenylyl cyclase activation. Unexpectedly, RGS2 reduces odorant-elicited cAMP production, not by acting on alpha-olf but by inhibiting the activity of adenylyl cyclase type III, the predominant adenylyl cyclase isoform in olfactory neurons. Furthermore, whole-cell voltage-clamp recordings of odorant-stimulated olfactory neurons indicate that endogenous RGS2 negatively regulates odorant-evoked intracellular signaling. These results revealed a mechanism for controlling the activities of adenylyl cyclases, which probably contributes to the ability of olfactory neurons to discriminate odors.
Wong et al. (2000) identified the presence of adenylyl cyclase 2 (603071), 3, and 4 (600292) in olfactory cilia. To evaluate the role of adenylate cyclase 3 in olfactory responses, Wong et al. (2000) disrupted the ADCY3 gene in mice. Electroolfactogram responses stimulated by either cAMP or inositol 1,4,5-triphosphate-inducing odorants were completely ablated in ADCY3 mutants, despite the presence of adenylyl cyclases 2 and 4 in olfactory cilia. Furthermore, ADCY3 mutants failed several olfaction-based behavioral tests, indicating that adenylyl cyclase 3 and cAMP signaling are critical for olfactory-dependent behavior.
Using a transgenic mouse line, Siljee et al. (2018) found Adcy3-positive primary cilia at a majority of Sim1 (603128)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN). Studies with human MCR4 (155541) showed that Adcy3 colocalized with MCR4 at primary cilia of neurons and regulated body weight in mice. Furthermore, inhibition of Adcy3 at primary cilia of Mc4r-expressing neurons of mice increased their food intake and was sufficient to cause obesity compared with controls.
Grarup et al. (2018) identified a splice site variant in the ADCY3 gene (600291.0001) with a minor allele frequency of 2.3% in a Greenlandic study population of 4,038 individuals. The 7 homozygous carriers had BMIs, body fat percentages, and waist circumferences that were all significantly greater than those of the remaining study population (BMIQ19; 617885), and an association with type 2 diabetes (T2D) was found that remained significant after adjustment for BMI. In addition, analysis of exome-sequencing data from 18,176 samples from the Accelerating Medicines Partnership Type 2 Diabetes Knowledge Portal (AMP-T2D) database identified heterozygosity for 7 predicted loss-of-function variants in ADCY3 in 8 individuals, and there was enrichment of carriers of ADCY3 variants among T2D cases compared to nondiabetic controls (odds ratio, 8.6; p = 0.044).
In 4 severely obese children from 3 consanguineous Pakistani families, Saeed et al. (2018) identified homozygosity for mutations in the ADCY3 gene (see, e.g., 600291.0002 and 600291.0003). In addition, an obese boy from a nonconsanguineous European American family was compound heterozygous for mutations in ADCY3 (600291.0004 and 600291.0005). All mutations occurred at highly conserved sites, and all segregated with disease in the respective families.
Pitman et al. (2014) reported a line of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Jll, with dominantly inherited resistance to diet-induced obesity. Jll mice had reduced body weight and fat mass and low basal insulin and glucose levels compared with wildtype controls. Both white and brown adipose tissue depots were smaller in Jll mice than wildtype. Jll mice fed a high-fat diet gained only slightly more weight than mice fed regular chow and were protected from hepatic lipid accumulation. Pitman et al. (2014) identified the Jll mutation as a met279-to-ile (M279I) substitution in the Adcy3 gene. The mutant Adcy3 protein was hyperactive in a cell-based reporter assay, producing elevated cAMP levels in response to forskolin compared with the wildtype protein, indicating that M279I is a gain-of-function mutation. Pitman et al. (2014) concluded that increased ADCY3 activity provides protection from diet-induced metabolic derangements.
In 7 Greenlandic individuals who had body mass indices (BMIs), body fat percentages, and waist circumferences that were significantly greater than those of control Greenlanders (BMIQ19; 617885), Grarup et al. (2018) identified homozygosity for a splice site mutation (c.2433-1G-A, NM_004036) in intron 13 of the ADCY3 gene, predicted to abolish the splice acceptor site of exon 14. The variant was present in the Greenlandic population at an overall minor allele frequency of 2.3%, with a frequency of 3.1% in those of Inuit ancestry, but was not found in non-Greenlandic populations in the gnomAD database. ADCY3 expression was markedly decreased in homozygous carriers of the variant, whereas heterozygous carriers showed intermediate expression levels. RNA analysis demonstrated that the homozygous carriers had a severely affected splicing pattern, consisting of 75% intron retention and 24% exon skipping. Intron retention was predicted to introduce a premature stop codon, rendering the isoform susceptible to nonsense-mediated decay.
In a 15-year-old Pakistani girl (family 1) with severe obesity (BMIQ19; 617885), Saeed et al. (2018) identified homozygosity for a 1-bp deletion (c.3315del, NM_004036.4), causing a frameshift predicted to result in a premature termination codon (Ile1106SerfsTer3). Her first-cousin unaffected parents and 2 unaffected sibs were heterozygous for the mutation, which was not found in the ExAC, dbSNP, or Exome Sequencing Project databases. Functional analysis in BHK cells showed a significant reduction in catalytic activity with the mutant compared to wildtype ADCY3.
In a 6-year-old Pakistani boy (family 2) with severe obesity (BMIQ19; 617885), Saeed et al. (2018) identified homozygosity for a splice site mutation (c.2578-1G-A, NM_004036.4), predicted to abolish the splice acceptor site of intron 15 and result in skipping of exon 16. His first-cousin parents were heterozygous for the mutation, which was not found in the ExAC, dbSNP, or Exome Sequencing Project databases. The parents, who had body mass indices (BMIs) of 35 and 30, respectively, belonged to the upper-middle class and their excess weight was believed to be due to a predilection for fat- and carbohydrate-enriched foods. Functional analysis in BHK cells showed a significant reduction in catalytic activity with the mutant compared to wildtype ADCY3. The mutation and family information were discordant in text, Figure 1, and supplementary information.
In an 11-year-old boy with severe obesity (BMIQ19; 617885) from a nonconsanguineous European American family (family 4), Saeed et al. (2018) identified compound heterozygosity for deletions in the ADCY3 gene: a 1-bp deletion (c.1268del, NM_004036.4), causing a frameshift predicted to result in a premature termination codon (Gly423AlafsTer19); and a 3-bp in-frame deletion (c.3354_3356del), resulting in deletion of 1 amino acid (phe1118del; 600291.0005). His unaffected parents were each heterozygous for 1 of the mutations. Functional analysis of the latter mutation in BHK cells demonstrated significant reduction in catalytic activity with the mutant compared to wildtype ADCY3.
For discussion of the 3-bp in-frame deletion (c.3354_3356del, NM_004036.4) in the ADCY3 gene, resulting in deletion of 1 amino acid (phe1118del), that was found in compound heterozygous state in an 11-year-old boy with severe obesity (BMIQ19; 617885) by Saeed et al. (2018), see 600291.0004.
Edelhoff, S., Villacres, E. C., Storm, D. R., Disteche, C. M. Mapping of adenylyl cyclase genes type I, II, III, IV, V, and VI in mouse. Mammalian Genome 6: 111-113, 1995. [PubMed: 7766992] [Full Text: https://doi.org/10.1007/BF00303253]
Gaudin, C., Homcy, C. J., Ishikawa, Y. Mammalian adenylyl cyclase family members are randomly located on different chromosomes. Hum. Genet. 94: 527-529, 1994. [PubMed: 7959689] [Full Text: https://doi.org/10.1007/BF00211020]
Grarup, N., Moltke, I., Andersen, M. K., Dalby, M., Vitting-Seerup, K., Kern, T., Mahendran, Y., Jorsboe, E., Larsen, C. V. L., Dahl-Petersen, I. K., Gilly, A., Suveges, D., Dedoussis, G., Zeggini, E., Pedersen, O., Andersson, R., Bjerregaard, P., Jorgensen, M. E., Albrechtsen, A., Hansen, T. Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Nature Genet. 50: 172-174, 2018. [PubMed: 29311636] [Full Text: https://doi.org/10.1038/s41588-017-0022-7]
Haber, N., Stengel, D., Defer, N., Roeckel, N., Mattei, M.-G., Hanoune, J. Chromosomal mapping of human adenylyl cyclase genes type III, type V and type VI. Hum. Genet. 94: 69-73, 1994. [PubMed: 8034296] [Full Text: https://doi.org/10.1007/BF02272844]
Ludwig, M.-G., Seuwen, K. Characterization of the human adenylyl cyclase gene family: cDNA, gene structure, and tissue distribution of the nine isoforms. J. Recept. Signal Transduct. Res. 22: 79-110, 2002. [PubMed: 12503609] [Full Text: https://doi.org/10.1081/rrs-120014589]
Pitman, J. L., Wheeler, M. C., Lloyd, D. J., Walker, J. R., Glynne, R. J., Gekakis, N. A gain-of-function mutation in adenylate cyclase 3 protects mice from diet-induced obesity. PLoS One 9: e110226, 2014. Note: Electronic Article. [PubMed: 25329148] [Full Text: https://doi.org/10.1371/journal.pone.0110226]
Saeed, S., Bonnefond, A., Tamanini, F., Mirza, M. U., Manzoor, J., Janjua, Q. M., Din, S. M., Gaitan, J., Milochau, A., Durand, E., Vaillant, E., Haseeb, A., and 16 others. Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nature Genet. 50: 175-179, 2018. [PubMed: 29311637] [Full Text: https://doi.org/10.1038/s41588-017-0023-6]
Siljee, J. E., Wang, Y., Bernard, A. A., Ersoy, B. A., Zhang, S., Marley, A., Von Zastrow, M., Reiter, J. F., Vaisse, C. Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nature Genet. 50: 180-185, 2018. [PubMed: 29311635] [Full Text: https://doi.org/10.1038/s41588-017-0020-9]
Sinnarajah, S., Dessauer, C. W., Srikumar, D., Chen, J., Yuen, J., Yilma, S., Dennis, J. C., Morrison, E. E., Vodyanoy, V., Kehrl, J. H. RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III. Nature 409: 1051-1055, 2001. [PubMed: 11234015] [Full Text: https://doi.org/10.1038/35059104]
Wong, S. T., Trinh, K., Hacker, B., Chan, G. C. K., Lowe, G., Gaggar, A., Xia, Z., Gold, G. H., Storm, D. R. Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron 27: 487-497, 2000. [PubMed: 11055432] [Full Text: https://doi.org/10.1016/s0896-6273(00)00060-x]
Yang, B., He, B., Abdel-Halim, S. M., Tibell, A., Brendel, M. D., Bretzel, R. G., Efendic, S., Hillert, J. Molecular cloning of a full-length cDNA for human type 3 adenylyl cyclase and its expression in human islets. Biochem. Biophys. Res. Commun. 254: 548-551, 1999. [PubMed: 9920776] [Full Text: https://doi.org/10.1006/bbrc.1998.9983]