Alternative titles; symbols
HGNC Approved Gene Symbol: PRKACG
Cytogenetic location: 9q21.11 Genomic coordinates (GRCh38): 9:69,012,504-69,014,113 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.11 | ?Bleeding disorder, platelet-type, 19 | 616176 | Autosomal recessive | 3 |
Beebe et al. (1990) reported the molecular cloning of a third isoform of the catalytic subunit of cAMP-dependent protein kinase (C-alpha (PRKACA; 601639) and C-beta (PRKACB; 176892) had previously been characterized). The third form, isolated from a human testis cDNA library and designated C-gamma, was clearly derived from a gene distinct from C-alpha and C-beta and showed tissue-specific expression. Whereas at the amino acid level C-alpha and C-beta showed 93% homology, C-gamma showed only about 80% homology to both C-alpha and C-beta.
Reinton et al. (1998) isolated the entire human PRKACG genomic sequence. The PRKACG gene is intronless, contains remnants of a poly(A) tail, is flanked by direct repeats, and is colinear with the PRKACA gene. Thus, the authors concluded that the PRKACG gene is a PRKACA-derived retroposon. Northern blot analysis detected PRKACG expression in fractionated germ cells of human testes.
Foss et al. (1991, 1992) mapped the gene for the subunit C-gamma to chromosome 9 by study of somatic cell hybrids. By in situ hybridization, they confirmed the assignment and regionalized the gene to chromosome 9q13.
Gross (2016) mapped the PRKACG gene to chromosome 9q21.11 based on an alignment of the PRKACG sequence (GenBank AJ001597) with the genomic sequence (GRCh38).
Among 304 Swiss individuals tested and genotyped, de Quervain and Papassotiropoulos (2006) found a significant association (p = 0.00008) between short-term episodic memory performance and genetic variations in a 7-gene cluster consisting of the ADCY8 (103070), PRKACG, CAMK2G (602123), GRIN2A (138253), GRIN2B (138252), GRM3 (601115), and PRKCA (176960) genes, all of which have well-established molecular and biologic functions in animal memory. Functional MRI studies in an independent set of 32 individuals with similar memory performance showed a correlation between activation in memory-related brain regions, including the hippocampus and parahippocampal gyrus, and genetic variability in the 7-gene cluster. De Quervain and Papassotiropoulos (2006) concluded that these 7 genes encode proteins of the memory formation signaling cascade that are important for human memory function.
Platelet-Type Bleeding Disorder 19
In 2 sibs, born of consanguineous parents of West Indian descent, with platelet-type bleeding disorder-19 (BDPLT19; 616176), Manchev et al. (2014) identified a homozygous missense mutation in the PRKACG gene (I74M; 176893.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Studies of patient platelets suggested that the mutation caused a loss of function, resulting in defective platelet activation, impaired cytoskeleton reorganization, and defective megakaryocyte proplatelet formation.
Associations Pending Confirmation
For discussion of a possible association between duplication of the PRKACG gene and 46,XY gonadal dysgenesis, see SRXY1 (400044).
In 2 sibs, born of consanguineous parents of West Indian descent, with platelet-type bleeding disorder-19 (BDPLT19; 616176), Manchev et al. (2014) identified a homozygous c.222C-G transversion in the PRKACG gene, resulting in an ile74-to-met (I74M) substitution at a conserved residue. A homozygous G559R variant was also identified in the GNE gene (603824). The mutations, which were found by whole-exome sequencing, both segregated with the disorder in the family. Neither variant was present in the dbSNP database. Patient platelets showed impaired activation and a defect in cytoskeleton reorganization with a decrease in actin polymerization. Patient platelets also showed increased levels of cAMP compared to controls, consistent with a loss of protein kinase A activity. Patient megakaryocytes and platelets had almost completely absent levels of filamin A (FLNA; 300017), putatively resulting from a loss of protective phosphorylation by protein kinase A. Patient megakaryocytes showed defective proplatelet formation that could be rescued by expression of wildtype PRKACG. As GNE was not associated with thrombocytopenia at that time, the GNE variant was not further studied. However, since biallelic GNE mutations have been identified in patients with congenital thrombocytopenia (THC12; 620757) with or without myopathy, the GNE variant in this family may have contributed to the phenotype (Futterer et al., 2018).
Beebe, S. J., Oyen, O., Sandberg, M., Froysa, A., Hansson, V., Jahnsen, T. Molecular cloning of a tissue-specific protein kinase (C gamma) from human testis--representing a third isoform for the catalytic subunit of cAMP-dependent protein kinase. Molec. Endocr. 4: 465-475, 1990. [PubMed: 2342480] [Full Text: https://doi.org/10.1210/mend-4-3-465]
de Quervain, D. J.-F., Papassotiropoulos, A. Identification of a genetic cluster influencing memory performance and hippocampal activity in humans. Proc. Nat. Acad. Sci. 103: 4270-4274, 2006. [PubMed: 16537520] [Full Text: https://doi.org/10.1073/pnas.0510212103]
Foss, K. B., Berube, D., Simard, J., Beebe, S. J., Sandberg, M., Grzeschik, K.-H., Gagne, R., Hansson, V., Jahnsen, T. Localization of the catalytic subunit C-gamma of cAMP-dependent protein kinase on human chromosome 9q13. (Abstract) Cytogenet. Cell Genet. 58: 1937-1938, 1991.
Foss, K. B., Simard, J., Berube, D., Beebe, S. J., Sandberg, M., Grzeschik, K.-H., Gagne, R., Hansson, V., Jahnsen, T. Localization of the catalytic subunit C-gamma of the cAMP-dependent protein kinase gene (PRKACG) to human chromosome region 9q13. Cytogenet. Cell Genet. 60: 22-25, 1992. [PubMed: 1339328] [Full Text: https://doi.org/10.1159/000133286]
Futterer, J., Dalby, A., Lowe, G. C., Johnson, B., Simpson, M. A., Motwani, J., Williams, M., Watson, S. P., Morgan, N. V. Mutation in GNE is associated with severe congenital thrombocytopenia. Blood 132: 1855-1858, 2018. [PubMed: 29941673] [Full Text: https://doi.org/10.1182/blood-2018-04-847798]
Gross, M. B. Personal Communication. Baltimore, Md. 8/31/2016.
Manchev, V. T., Hilpert, M, Berrou, E., Elaib, Z., Aouba, A., Boukour, S., Souquere, S., Pierron, G., Rameau, P., Andrews, R., Lanza, F., Bobe, R., Vainchenker, W., Rosa, J.-P., Bryckaert, M., Debili, N., Favier, R., Raslova, H. A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene. Blood 124: 2554-2563, 2014. [PubMed: 25061177] [Full Text: https://doi.org/10.1182/blood-2014-01-551820]
Reinton, N., Haugen, T. B., Orstavik, S., Skalhegg, B. S., Hansson, V., Jahnsen, T., Tasken, K. The gene encoding the C gamma catalytic subunit of cAMP-dependent protein kinase is a transcribed retroposon. Genomics 49: 290-297, 1998. [PubMed: 9598317] [Full Text: https://doi.org/10.1006/geno.1998.5240]