Alternative titles; symbols
HGNC Approved Gene Symbol: PRKRA
SNOMEDCT: 722435003;
Cytogenetic location: 2q31.2 Genomic coordinates (GRCh38) : 2:178,431,414-178,451,175 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.2 | Dystonia 16 | 612067 | Autosomal recessive | 3 |
The double-stranded RNA (dsRNA)-activated protein kinase PKR (176871) is a mediator of the effects of interferon (see 107470), particularly its antiviral activities. PKR has also been implicated in the onset of differentiation. Based on its interaction with PKR, Patel and Sen (1998) cloned PACT cDNA. The PACT cDNA encodes a deduced 313-amino acid polypeptide that contains 3 motifs resembling the dimerization motifs present in PKR and other dsRNA-binding proteins. Northern blot analysis revealed that PACT is expressed as a 2.0-kb mRNA in a variety of human cell lines.
Ito et al. (1999) cloned the mouse homolog, which they called RAX, from a mouse Il3 (147740)-dependent cell cDNA library using the yeast 2-hybrid interactive cloning system. They showed that the mouse and human sequences share 98% identity. Northern blot analysis detected expression of RAX in all tissues tested. Western blot analysis showed a 35-kD protein expressed in cell lines derived from several mammalian species.
By biochemical studies, Patel and Sen (1998) determined that PACT binds to both PKR and dsRNA. PACT activates PKR in a dsRNA-independent manner.
Using cell culture and several in vitro biochemical techniques, Ito et al. (1999) found that Il3 deprivation as well as diverse cell stress treatments known to inhibit protein synthesis induces the rapid serine phosphorylation of mouse RAX, followed by RAX-PKR association and activation of PKR.
Kok et al. (2011) noted that the virus sensor RIGI (DDX58; 609631) shares structural similarity with DICER (606241), an RNase III-type nuclease that mediates RNA interference and requires dsRNA-binding partners, such as PACT, for optimal activity. They showed that PACT physically bound to the C-terminal repression domain of RIGI and stimulated RIGI-induced type I interferon (e.g., IFNB1; 147640) production. PACT potentiated RIGI activation by poly(I:C) and helped sustain antiviral responses. Kok et al. (2011) concluded that PACT has an important role in initiating and sustaining RIGI-dependent antiviral responses.
Scott (2001) mapped the PRKRA gene based on sequence similarity between PRKA (GenBank AF072860) and a BAC clone (GenBank AC009948) sequence localized to 2q31.3.
In affected members of 2 unrelated Brazilian families with early-onset dystonia-16 (DYT16; 612067), Camargos et al. (2008) identified a homozygous missense mutation in the PRKRA gene (P222L; 603424.0001). Haplotype analysis indicated a founder effect.
Zech et al. (2014) identified a homozygous P222L mutation in the PRKRA gene in 2 Polish brothers with DYT16. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Haplotype analysis indicated identity by state with the Brazilian patients who carried this mutation (Camargos et al., 2008), consistent with a founder effect. Functional studies of the variant were not performed. No additional PRKRA mutations were found in 10 German patients with generalized dystonia. Three heterozygous variants (T34S, N102S, and c.-14A-G) in the PRKRA gene were found in 3 of 329 patients with mainly adult-onset focal or segmental dystonia, but the pathogenicity of these heterozygous variants was unclear.
Rowe et al. (2006) found that Pact-null mice were born at the expected frequency. They were smaller than wildtype mice, but appeared relatively normal except for the craniofacial area, which had a rounded rostrum, shortened nose, hypoplastic turbinates, and small outer ear. Microscopic examination of the ear tissues revealed smaller pinna and external auditory canals and malformed ossicles, as well as small middle ear space and bulla. Cochlea appeared normal. The ear malformations were accompanied by hearing defects.
Peters et al. (2009) found that Pact -/- mice grew more slowly than Pact +/- or wildtype littermates. Pact -/- adult females showed developmental defects in ovaries and mammary glands and were completely sterile, and Pact -/- males showed reduced fertility. Peters et al. (2009) found that these defects were due to anterior lobe-specific hypoplasia and inadequate release of pituitary hormones. Examination of anterior pituitaries revealed that the hypoplasia severely decreased the number of lactotrophs and more weakly decreased the numbers of corticotrophs, gonadotrophs, and somatotrophs. Thyrotroph numbers were normal. The reduction in pituitary cell numbers appeared to be due to a defect in cell proliferation rather than elevated apoptosis. Unlike humans, in which pituitary development is normally completed in utero, mice undergo a second wave of pituitary proliferation at birth that continues for 3 to 4 weeks. Only this second wave of proliferation was affected in Pact -/- mice.
In affected members of 2 unrelated Brazilian families with dystonia-16 (DYT16; 612067), Camargos et al. (2008) identified a homozygous 665C-T transition in exon 7 of the PRKRA gene, resulting in a pro222-to-leu (P222L) substitution. An additional unrelated Brazilian patient with dystonia was also found to carry the mutation. Age at onset ranged from 7 to 18 years. The disorder was progressive and characterized by lower limb dystonia and gait abnormalities, spasmodic dysphonia, and torticollis. Some patients had bradykinesia. Haplotype analysis suggested a founder effect.
Zech et al. (2014) identified homozygosity for the P222L mutation in 2 Polish brothers with DYT16. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the dbSNP and 1000 Genomes Project databases and was not present in the Exome Sequencing Project database, in 2,002 in-house control exomes, or in 376 controls. Haplotype analysis indicated identity by state with the Brazilian patients who carried this mutation (Camargos et al., 2008), consistent with a founder effect. Functional studies of the variant were not performed.
In a 9-year-old German boy with dystonia-16 (DYT16; 612067), Seibler et al. (2008) identified a heterozygous 2-bp deletion (266delAT) in exon 3 of the PRKRA gene, predicted to result in a frameshift and premature termination. He presented with early-onset dystonia of the legs that spread gradually over a few years. There was no family history of movement disorders. Although a second pathogenic PRKRA mutation was not identified, Seibler et al. (2008) postulated that there may be a mutation in noncoding gene regions or that there may be a gene dosage effect. Alternatively, the heterozygous mutation may be pathogenic in itself.
Camargos, S., Scholz, S., Simon-Sanchez, J., Paisan-Ruiz, C., Lewis, P., Hernandez, D., Ding, J., Gibbs, J. R., Cookson, M. R., Bras, J., Guerreiro, R., Oliveira, C. R., Lees, A., Hardy, J., Cardoso, F., Singleton, A. B. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol. 7: 207-215, 2008. [PubMed: 18243799] [Full Text: https://doi.org/10.1016/S1474-4422(08)70022-X]
Ito, T., Yang, M., May, W. S. RAX, a cellular activator for double-stranded RNA-dependent protein kinase during stress signaling. J. Biol. Chem. 274: 15427-15432, 1999. [PubMed: 10336432] [Full Text: https://doi.org/10.1074/jbc.274.22.15427]
Kok, K.-H., Lui, P.-Y., Ng, M.-H. J., Siu, K.-L., Au, S. W. N., Jin, D.-Y. The double-stranded RNA-binding protein PACT functions as a cellular activator of RIG-I to facilitate innate antiviral response. Cell Host Microbe 9: 299-309, 2011. [PubMed: 21501829] [Full Text: https://doi.org/10.1016/j.chom.2011.03.007]
Patel, R. C., Sen, G. C. PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J. 17: 4379-4390, 1998. [PubMed: 9687506] [Full Text: https://doi.org/10.1093/emboj/17.15.4379]
Peters, G. A., Seachrist, D. D., Keri, R. A., Sen, G. C. The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary proliferation. Proc. Nat. Acad. Sci. 106: 10696-10701, 2009. [PubMed: 19541653] [Full Text: https://doi.org/10.1073/pnas.0900735106]
Rowe, T. M., Rizzi, M., Hirose, K., Peters, G. A., Sen, G. C. A role of the double-stranded RNA-binding protein PACT in mouse ear development and hearing. Proc. Nat. Acad. Sci. 103: 5823-5828, 2006. [PubMed: 16571658] [Full Text: https://doi.org/10.1073/pnas.0601287103]
Scott, A. F. Personal Communication. Baltimore, Md. 2001.
Seibler, P., Djarmati, A., Langpap, B., Hagenah, J., Schmidt, A., Bruggemann, N., Siebner, H., Jabusch, H.-C., Altenmuller, E., Munchau, A., Lohmann, K., Klein, C. A heterozygous frameshift mutation in PRKRA (DYT16) associated with generalised dystonia in a German patient. Lancet Neurol. 7: 380-381, 2008. [PubMed: 18420150] [Full Text: https://doi.org/10.1016/S1474-4422(08)70075-9]
Zech, M., Castrop, F., Schormair, B., Jochim, A., Wieland, T., Gross, N., Lichtner, P., Peters, A., Gieger, C., Meitinger, T., Strom, T. M., Oexle, K., Haslinger, B., Winkelmann, J. DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family. Mov. Disord. 29: 1504-1510, 2014. [PubMed: 25142429] [Full Text: https://doi.org/10.1002/mds.25981]