Alternative titles; symbols
HGNC Approved Gene Symbol: ADCY6
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38): 12:48,766,194-48,789,974 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.12 | Lethal congenital contracture syndrome 8 | 616287 | Autosomal recessive | 3 |
ADCY6 belongs to the adenylate cyclase (EC 4.6.1.1) family of enzymes responsible for the synthesis of cAMP (Ludwig and Seuwen, 2002).
By semiquantitative RT-PCR, Ludwig and Seuwen (2002) found that ADCY6 was mainly expressed in heart, kidney, prostate, testis, ovary, small intestine, colon, and at lower levels in brain, placenta, lung, pancreas, spleen, and thymus. ADCY6 was not detected in liver.
Ludwig and Seuwen (2002) determined that the ADCY6 gene contains 21 exons and spans 17.9 kb.
By Southern blot analysis of somatic cell hybrid DNAs, Gaudin et al. (1994) mapped the ADCY6 gene to chromosome 12. Using isotopic in situ hybridization, Haber et al. (1994) mapped the ADCY6 gene to 12q12-q13. By fluorescence in situ hybridization, Edelhoff et al. (1995) confirmed the assignment of ADCY6 to 12q13 and demonstrated that the homologous mouse gene is located on chromosome 15 in the F region.
In 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome (LCCS8; 616287), Laquerriere et al. (2014) identified a homozygous missense mutation in the ADCY6 gene (R1116C; 600294.0001). The parents were heterozygous for the mutation.
By whole-exome sequencing, Gonzaga-Jauregui et al. (2015) identified a homozygous missense mutation (Y992C; 600294.0002) in the ADCY6 gene in a male patient (patient 1163) with LCCS8.
By trio-based whole-exome sequencing, Agolini et al. (2020) identified compound heterozygous mutations in the ADCY6 gene (600294.0003; 600294.0004) in a female patient with LCCS8. Each parent was heterozygous for one of the mutations.
Laquerriere et al. (2014) knocked down ADCY6 orthologs in zebrafish. The morphants showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth.
In 2 sibs from a consanguineous family (A649) with lethal arthrogryposis multiplex congenita (LCCS8; 616287), Laquerriere et al. (2014) identified a homozygous c.3346C-T transition (c.3346C-T, NM_015270) in exon 20 of the ADCY6 gene, resulting in an arg1116-to-cys (R1116C) substitution. The parents were heterozygous for the mutation, which was not found in the Exome Variant Server or the dbSNP (build 138) databases. Knockdown of ADCY6 orthologs in zebrafish led to a similar phenotype.
In a male patient (patient 1163) with lethal arthrogryposis multiplex congenita (LCCS8; 616287), Gonzaga-Jauregui et al. (2015) identified a homozygous tyr992-to-cys (Y992C) mutation in the ADCY6 gene. The mutation was identified by whole-exome sequencing. Functional studies were not performed.
Agolini et al. (2020) performed molecular modeling of mutations in the ADCY6 gene and predicted that the Y992C mutation impairs both stimulation of ADCY6 by G proteins and dimerization of the AC domains.
In a female patient with lethal arthrogryposis multiplex congenita (LCCS8; 616287), Agolini et al. (2020) identified compound heterozygous mutations in the ADCY6 gene: a splicing mutation (c.1535+1G-A, NM_015270.4) in intron 7, and a c.3007G-A transition, resulting in a glu1003-to-lys (D1003K; 600294.0004) substitution at a conserved residue in the C2 domain. The mutations were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. The D1003K variant was not present in the gnomAD database. Molecular modeling predicted that the D1003K mutation impairs both stimulation of ADCY6 by G proteins and dimerization of the AC domains.
For discussion of the c.3007G-A transition (c.3007G-A, NM_015270.4) in the ADCY6 gene, resulting in a glu1003-to-lys (D1003K) substitution, that was found in compound heterozygous state in a patient with arthrogryposis multiplex congenita (LCCS8; 616287) by Agolini et al. (2020), see 600294.0003.
Agolini, E., Cherchi, C., Bellacchio, E., Martinelli, D., Cocciadiferro, D., Cutrera, R., Chiarini Testa, M. B., Barone, C., Bianca, S., Novelli, A. Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6. Clin. Genet. 97: 649-654, 2020. [PubMed: 31846058] [Full Text: https://doi.org/10.1111/cge.13691]
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]
Gonzaga-Jauregui, C., Harel, T., Gambin, T., Kousi, M., Griffin, L. B., Francescatto, L., Ozes, B., Karaca, E., Jhangiani, S. N., Bainbridge, M. N., Lawson, K. S., Pehlivan, D., and 23 others. Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep. 12: 1169-1183, 2015. [PubMed: 26257172] [Full Text: https://doi.org/10.1016/j.celrep.2015.07.023]
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]
Laquerriere, A., Maluenda, J., Camus, A., Fontenas, L., Dieterich, K., Nolent, F., Zhou, J., Monnier, N., Latour, P., Gentil, D., Heron, D., Desguerres, I., and 48 others. Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. Hum. Molec. Genet. 23: 2279-2289, 2014. [PubMed: 24319099] [Full Text: https://doi.org/10.1093/hmg/ddt618]
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]