Alternative titles; symbols
HGNC Approved Gene Symbol: PRKACB
Cytogenetic location: 1p31.1 Genomic coordinates (GRCh38): 1:84,078,079-84,238,498 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p31.1 | Cardioacrofacial dysplasia 2 | 619143 | Autosomal dominant; Somatic mosaicism | 3 |
The PRKACB gene encodes a catalytic subunit of cAMP-dependent protein kinase (PKA), a tetrameric holoenzyme composed of 2 catalytic and 2 regulatory subunits (summary by Soberg et al., 2017). Other catalytic subunits are encoded by PRKACA (601639) and PRKACG (176893).
Soberg et al. (2017) stated that the main splice variant of human PRKACB, C-beta-1, is a 350-residue protein with 93% sequence identity to C-alpha-1, encoded by PRKACA.
Soberg et al. (2017) stated that the PRKACB gene has 4 alternative 5-prime exons, a cassette of short exons denoted a, b, and c, and nine 3-prime exons (2 through 10). Alternative use of exons 5-prime to exon 2 of PRKACB gives rise to at least 10 different catalytically active C-beta proteins. Exons 2 through 10 are expressed and translated in all known catalytically active C-beta protein isoforms. The intron-exon structure of exons 2 through 10 is conserved throughout vertebrate evolution.
Soberg et al. (2017) stated that PRKACA and PRKACB are highly conserved paralogous genes that arose from a gene duplication event around the time of evolution of the first vertebrate species, approximately 500 million years ago.
Berube et al. (1991) assigned the catalytic subunit C-beta of PKA to human chromosome 1 by Southern blot analysis of somatic cell hybrids. By in situ hybridization, the gene was localized to chromosome 1p36.1. (Also see Simard et al. (1992).)
Stumpf (2020) mapped the PRKACB gene to chromosome 1p31.1 based on an alignment of the PRKACB sequence (GenBank BC016285) with the genomic sequence (GRCh38).
In 4 unrelated probands with cardioacrofacial dysplasia (CAFD2; 619143), Palencia-Campos et al. (2020) identified heterozygosity for de novo missense mutations in the PRKACB gene (601639.0001-601639.0004) that were not found in the gnomAD database. Functional analysis demonstrated that the mutant PKA holoenzymes are more sensitive to activation by cAMP than wildtype proteins. In addition, the variants inhibited hedgehog (see 600725) signaling, which the authors suggested as an underlying mechanism for the observed developmental defects.
In an 18-year-old Danish woman (P4) with cardioacrofacial dysplasia (CAFD2; 619143), Palencia-Campos et al. (2020) identified heterozygosity for a de novo c.703G-C transversion (c.703G-C, NM_002731.3) in the PRKACB gene, resulting in a gly235-to-arg (G235R) substitution at a highly conserved residue at a tethering surface that interacts with regulatory proteins. The mutation was not found in the gnomAD database. Bioluminescence resonance energy transfer analysis showed a dramatic increase in sensitivity to cAMP with the mutant holoenzyme compared to the wildtype PKA holoenzyme, and PepTag assay in transfected HEK293 cells showed increased kinase activity with the G235R mutant at low cAMP concentrations compared to wildtype protein. Analysis of hedgehog (see 600725) pathway signaling in retrotransduced NIH 3T3 cells after stimulation with the SMO (601500) agonist SAG revealed that the G235R mutant impairs SAG-mediated inactivation of PKA.
In a 15-year-old French girl (P5) with cardioacrofacial dysplasia (CAFD2; 619143), Palencia-Campos et al. (2020) identified heterozygosity for a de novo c.161C-T transition (c.161C-T, NM_002731.3) in the PRKACB gene, resulting in a ser54-to-leu (S54L) substitution at a highly conserved residue. The mutation, which was not found in the gnomAD database, showed a variant allele fraction of 0.32, and eletropherograms confirmed mosaicism in the proband.
In a 20-year-old French man (P6) with cardioacrofacial dysplasia (CAFD2; 619143), Palencia-Campos et al. (2020) identified heterozygosity for a de novo c.263A-G transition (c.263A-G, NM_002731.3) in the PRKACB gene, resulting in a his88-to-arg (H88R) substitution at a highly conserved residue. The mutation was not found in the gnomAD database. Bioluminescence resonance energy transfer analysis showed a dramatic increase in sensitivity to cAMP with the mutant holoenzyme compared to the wildtype PKA holoenzyme, which was confirmed using fluorescence polarization assays.
In a 41-year-old Australian woman (P7) with cardioacrofacial dysplasia (CAFD2; 619143), Palencia-Campos et al. (2020) identified heterozygosity for a de novo c.262C-A transversion (c.262C-A, NM_002731.3) in the PRKACB gene, resulting in a his88-to-asn (H88N) substitution at a highly conserved residue. The mutation was not found in her unaffected parents or the gnomAD database.
Berube, D., Simard, J., Sandberg, M., Grzeschik, K.-H., Gagne, R., Hansson, V., Jahnsen, T. Assignment of the gene encoding the catalytic subunit C(beta) of cAMP-dependent protein kinase to the p36 band on chromosome 1. (Abstract) Cytogenet. Cell Genet. 58: 1850 only, 1991.
Palencia-Campos, A., Aoto, P. C., Machal, E. M. F., Rivera-Barahona, A., Soto-Bielicka, P., Bertinetti, D., Baker, B., Vu, L., Piceci-Sparascio, F., Torrente, I., Boudin, E., Peeters, S., and 30 others. Germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome. Am. J. Hum. Genet. 107: 977-988, 2020. [PubMed: 33058759] [Full Text: https://doi.org/10.1016/j.ajhg.2020.09.005]
Simard, J., Berube, D., Sandberg, M., Grzeschik, K.-H., Gagne, R., Hansson, V., Jahnsen, T. Assignment of the gene encoding the catalytic subunit C-beta of cAMP-dependent protein kinase to the p36 band on chromosome 1. Hum. Genet. 88: 653-657, 1992. [PubMed: 1551670] [Full Text: https://doi.org/10.1007/BF02265292]
Soberg, K., Moen, L. V., Skalhegg, B. S., Laerdahl, J. K. Evolution of the cAMP-dependent protein kinase (PKA) catalytic subunit isoforms. PLoS One 12: e0181091, 2017. Note: Electronic Article. [PubMed: 28742821] [Full Text: https://doi.org/10.1371/journal.pone.0181091]
Stumpf, A. M. Personal Communication. Baltimore, Md. 12/28/2020.