Alternative titles; symbols
HGNC Approved Gene Symbol: ADCY1
Cytogenetic location: 7p12.3 Genomic coordinates (GRCh38): 7:45,574,140-45,723,116 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p12.3 | ?Deafness, autosomal recessive 44 | 610154 | Autosomal recessive | 3 |
ADCY1 is the founding member of the adenylate cyclase (EC 4.6.1.1) family of enzymes responsible for the synthesis of cAMP (Ludwig and Seuwen, 2002).
The neural-specific, calmodulin-sensitive adenylyl cyclase (type I), which was first cloned from bovine brain, has been implicated in learning and memory. Villacres et al. (1993) cloned the gene for human fetal brain type I adenylyl cyclase.
By database analysis and PCR of human embryonic kidney cell cDNA, Ludwig and Seuwen (2002) cloned full-length ADCY1. The deduced protein contains 1,119 amino acids. Semiquantitative RT-PCR detected ADCY1 highly expressed in peripheral blood leukocytes. Moderate or low ADCY1 levels were detected in brain and most other tissues examined except thymus, prostate, and small intestine.
Santos-Cortez et al. (2014) showed that Adcy1 expression in the mouse is present throughout inner ear development and that the protein localizes to the cytoplasm of supporting cells and hair cells of the cochlea vestibule, as well as to the cochlear hair cell nuclei and stereocilia.
Ludwig and Seuwen (2002) determined that the ADCY1 gene contains 20 exons and spans 145.5 kb. The splice donor of intron 14 does not follow the usual splice site rule.
By in situ hybridization, Villacres et al. (1993) mapped the ADCY1 gene to 7p13-p12. Gaudin et al. (1994) likewise mapped the ADCY1 gene to chromosome 7 by Southern blot analysis of somatic cell hybrid DNAs.
By fluorescence in situ hybridization, Edelhoff et al. (1995) mapped the mouse homolog to chromosome 11 in the A2 region.
In transgenic mice with specific overexpression of Adcy1 in the forebrain, Wang et al. (2004) found a tendency toward increased long-term potentiation, increased memory for object recognition, and slower rates of extinction for contextual memory compared to wildtype mice. Expression of ERK/MAPK (see 176948) signaling was increased in transgenic mice.
In affected members of a Pakistani family with autosomal recessive nonsyndromic hearing loss (DFNB44; 610154), originally reported by Ansar et al. (2004), Santos-Cortez et al. (2014) identified a homozygous truncating mutation in the ADCY1 gene (103072.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with hearing loss in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 650 ethnically matched control chromosomes.
The somatosensory cortex of mice displays a patterned, nonuniform distribution of neurons in layer IV called the 'barrelfield.' Thalamocortical afferents (TCAs) that terminate in layer IV are segregated such that each barrel, a readily visible cylindrical array of neurons surrounding a cell-sparse center, represents a distinct receptive field. TCA arbors are confined to the barrel hollow and synapse on barrel-wall neurons whose dendrites are oriented toward the center of the barrel. Mice homozygous for the 'barrelless' (brl) mutation, which occurred spontaneously in Switzerland, failed to develop this patterned distribution of neurons, but still displayed normal topologic organization of the somatosensory cortex (Welker et al., 1996). Despite the absence of barrels and the overlapping zones of TCA arborization, the size of individual whisker representations, as judged by 2-deoxyglucose uptake, was similar to that of wildtype mice. Abdel-Majid et al. (1998) identified Adcy1 as the gene disrupted in brl mutant mice by fine mapping of proximal chromosome 11, enzyme assay, mutation analysis, and examination of mice homozygous for a targeted disruption of Adcy1. These results provided the first evidence for involvement of cAMP signaling pathways in pattern formation of the brain.
Wei et al. (2002) found that wildtype, Ac1-null, Ac8 (ADCY8; 103070)-null, and Ac1-Ac8 double knockout mice were indistinguishable in their response to acute pain. However, behavioral responses to inflammatory stimuli were significantly reduced in mice lacking Ac1 or Ac8, and more profoundly compromised in Ac1 and Ac8 double knockout mice. Both Ac1 and Ac8 were expressed at high levels in 2 pain-related forebrain areas, the anterior cingulate cortex and the insular cortex, and at a low level in the spinal cord. Injection of an adenylyl cyclase activator in the anterior cingulate cortex rescued the response to noxious stimuli in Ac1-Ac8 double knockout mice.
In barrelless mice, Lu et al. (2003) found a decrease of functional AMPA receptors (see, e.g., 138248), an impairment in long-term potentiation and long-term depression at thalamocortical synapses, and a reduction in protein kinase A (PKA; see 176911) activity. The authors suggested that AMPA receptor trafficking plays a role in sensory map formation and is controlled through a signaling pathway that links calcium influx to PKA through ADCY1. Barrelless mice, which lack ADCY1, have a disruption in the PKA signaling pathway that regulates the synaptic plasticity needed for cortical map formation.
In affected members of a Pakistani family with autosomal recessive nonsyndromic hearing loss (DFNB44; 610154), originally reported by Ansar et al. (2004), Santos-Cortez et al. (2014) identified a homozygous c.3112C-T transition in the ADCY1 gene (103072.0001), resulting in an arg1038-to-ter (R1038X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with hearing loss in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 650 ethnically matched control chromosomes. The mutation was predicted to cause the loss of 82 amino acids that form beta sheets of the cytoplasmic C terminus, including a highly conserved motif at the C2 domain at amino acids 1037-1053, as well as the loss of a calmodulin-interacting site. Arg1038 was predicted to lie within the AC catalytic domain and to participate in ATP binding. ADCY1 truncated COS-7 cells did not localize properly to microvilli, suggesting that these conserved elements within the C terminus are necessary not only for catalysis but also for membrane targeting. Santos-Cortez et al. (2014) generated gene-copy-specific zebrafish morphants, which showed gross hearing defects.
Abdel-Majid, R. M., Leong, W. L., Schalkwyk, L. C., Smallman, D. S., Wong, S. T., Storm, D. R., Fine, A., Dobson, M. J., Guernsey, D. L., Neumann, P. E. Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nature Genet. 19: 289-291, 1998. [PubMed: 9662407] [Full Text: https://doi.org/10.1038/980]
Ansar, M., Chahrour, M. H., Amin ud Din, M., Arshad, M., Haque, S., Pham, T. L., Yan, K., Ahmad, W., Leal, S. M. DFNB44, a novel autosomal recessive non-syndromic hearing impairment locus, maps to chromosome 7p14.1-q11.22. Hum. Hered. 57: 195-199, 2004. [PubMed: 15583425] [Full Text: https://doi.org/10.1159/000081446]
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]
Lu, H.-C., She, W.-C., Plas, D. T., Neumann, P. E., Janz, R., Crair, M. C. Adenylyl cyclase I regulates AMPA receptor trafficking during mouse cortical 'barrel' map development. Nature Neurosci. 6: 939-947, 2003. [PubMed: 12897788] [Full Text: https://doi.org/10.1038/nn1106]
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]
Santos-Cortez, R. L. P., Lee, K., Giese, A. P., Ansar, M., Amin-Ud-Din, M., Rehn, K., Wang, X., Aziz, A., Chiu, I., Ali, R. H., Smith, J. D., University of Washington Center for Mendelian Genomics, Shendure, J., Bamshad, M., Nickerson, D. A., Ahmed, Z. M., Ahmad, W., Riazuddin, S., Leal, S. M. Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. Hum. Molec. Genet. 23: 3289-3298, 2014. [PubMed: 24482543] [Full Text: https://doi.org/10.1093/hmg/ddu042]
Villacres, E. C., Xia, Z., Bookbinder, L. H., Edelhoff, S., Disteche, C. M., Storm, D. R. Cloning, chromosomal mapping, and expression of human fetal brain type I adenylyl cyclase. Genomics 16: 473-478, 1993. [PubMed: 8314585] [Full Text: https://doi.org/10.1006/geno.1993.1213]
Wang, H., Ferguson, G. D., Pineda, V. V., Cundiff, P. E., Storm, D. R. Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nature Neurosci. 7: 635-642, 2004. [PubMed: 15133516] [Full Text: https://doi.org/10.1038/nn1248]
Wei, F., Qiu, C.-S., Kim, S. J., Muglia, L., Maas, J. W., Jr., Pineda, V. V., Xu, H.-M., Chen, Z.-F., Storm, D. R., Muglia, L. J., Zhuo, M. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36: 713-726, 2002. [PubMed: 12441059] [Full Text: https://doi.org/10.1016/s0896-6273(02)01019-x]
Welker, E., Armstrong-James, M., Bronchti, G., Ourednik, W., Gheorghita-Baechler, F., Dubois, R., Guernsey, D. L., Van der Loos, H., Neumann, P. E. Altered sensory processing in the somatosensory cortex of the mutant mouse barrelless. Science 271: 1864-1867, 1996. [PubMed: 8596955] [Full Text: https://doi.org/10.1126/science.271.5257.1864]