Alternative titles; symbols
HGNC Approved Gene Symbol: ALPK1
SNOMEDCT: 771471002;
Cytogenetic location: 4q25 Genomic coordinates (GRCh38) : 4:112,297,369-112,442,621 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q25 | ROSAH syndrome | 614979 | Autosomal dominant | 3 |
ALPK1 is a member of the family of atypical protein kinases, which have a unique catalytic domain architecture (Middelbeek et al., 2010).
Unlike most eukaryotic kinases, many alpha kinases recognize phosphorylation sites in which the surrounding peptides have an alpha-helical conformation. By EST database searching for homologs of the alpha kinase EEF2K (606968), Ryazanov et al. (1999) identified LAK, which they termed 'chromosome 4 kinase.'
By screening for cDNAs with the potential to encode large proteins expressed in brain, Nagase et al. (2000) identified a partial cDNA encoding LAK, which they called KIAA1527. Using RT-PCR analysis, they detected moderate expression of LAK in all tissues tested except liver, where expression was high.
By quantitative RT-PCR in human donor eye tissue, Williams et al. (2019) observed increased expression of AKPK1 in the retinal pigment epithelium (RPE) and optic nerve compared with the retina. RT-PCR performed on spleen tissue samples confirmed expression of ALPK1 in normal spleen. In the mouse retina, confocal microscopy showed that Alpk1 localized to the area of basal bodies in connecting cilia of the photoreceptors and to the RPE, as well as to the inner and outer plexiform layers. In the connecting cilium region, Alpk1 localized to the basal body of the photoreceptor cilium and adjacent centriole region. In mouse skin, Alpk1 was present in the sweat glands, especially in myoepithelial cells. There was also broad expression in other mouse tissues. Immunofluorescence studies in ARPE19 cells demonstrated localization of ALPK1 in the spindle poles at metaphase, and in centrosomes of cells during interphase. Super-resolution confocal imaging in immunostained serum-starved ARPE19 cells showed the presence of ALPK1 in the base of primary cilia. The authors suggested that ALPK1 might play a role in centrosome biology.
In a review, Middelbeek et al. (2010) stated that the human genome contains 6 alpha kinases. EEF2K represents the oldest alpha kinase within the vertebrates. The alpha kinase domain present at the extreme C terminus of ALPK1, ALPK2 (619965), and ALPK3 (617608) is particularly well conserved between ALPK2 and ALPK3.
By genomic sequence analysis, Ryazanov et al. (1999) and Nagase et al. (2000) mapped the ALPK1 gene to chromosome 4.
Rashid et al. (2019) stated that the ALPK1 gene is located on chromosome 4q25.
Zhou et al. (2018) found that ADP-beta-D-manno-heptose (ADP-Hep), but not other heptose metabolites, could enter host cytosol to activate NF-kappa-B (see 164011). A CRISPR-Cas9 screen showed that activation of NF-kappa-B by ADP-Hep involves an ALPK1-TIFA (609028) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. The bacterial metabolite D-glycero-beta-D-manno-heptose 1,7-bisphosphonate (HBP) was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during bacterial infection induced Alpk1-dependent inflammation in mice. Zhou et al. (2018) concluded that their findings identified ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively.
Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Migraine Headache Syndrome
In all 16 affected individuals from 5 unrelated families with retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (ROSAH; 614979), Williams et al. (2019) identified heterozygosity for the same missense mutation in the ALPK1 gene (T237M; 607347.0001). The mutation segregated with disease in all families and was not found in the gnomAD database.
In 2 unrelated Chinese girls with ROSAH syndrome, Zhong et al. (2020) identified heterozygosity for the previously reported recurrent T237M mutation in the ALPK1 gene. The mutation arose de novo in both probands.
Kozycki et al. (2022) reported molecular findings in 21 patients from 13 unrelated families with ROSAH syndrome. Twenty of the patients were heterozygous for the recurrent T237M mutation in the ALPK1 gene, and 1 patient (patient 13.1) was heterozygous for a Y254C (607347.0002) mutation. In transfected HEK293T cells, both mutants increased constitutive NF-kappa-B activity via luciferase assay and had increased constitutive STAT1 (600555) activation compared to wildtype. In ADP-heptose-stimulated fibroblasts from the patient with the Y254C mutation and a patient with the T237M mutation, phosphorylation of members of the canonical NF-kappa-B pathway, including I-kappa-B alpha (NFKBIA; 164008), IKK-alpha/beta (CHUK; 600664/IKBKB; 603258), p38 (MAPK14; 600289), and JNK (601158), was increased compared to wildtype. Kozycki et al. (2022) concluded that the Y254C and T237M mutations in the ALPK1 gene result in increased NF-kappa-B signaling and STAT1 phosphorylation.
Somatic Mutation in Spiradenoma and Spiradenocarcinoma
In biopsy specimens from skin adnexal tumors that were negative for mutation in the CYLD gene (605018), Rashid et al. (2019) identified a recurrent somatic missense mutation (V1092A) in the alpha-kinase domain of the ALPK1 gene in 7 of 16 spiradenoma samples as well as in 2 of 8 high-grade and 2 of 6 low-grade spiradenocarcinoma samples. The variant was confirmed in 6 of 10 additional spiradenoma tumors. In several cases, the V1092A variant was present in adjacent morphologically normal tissue, at an average mutant allele fraction of 0.32. In addition, the mutation was observed in sequence data from benign precursor regions, suggesting that V1092A may be an early founder mutation or associated with a field change. Functional analysis in transfected cancer cell lines showed that the V1092A variant increased NFKB (see 164011) pathway activity to a considerably higher level than wildtype ALPK1.
Chen and Xu (2011) found that Alpk1 -/- mice had severe defects in motor coordination compared with wildtype. However, cerebellar architecture, Purkinje cell morphology, and electrophysiology of Purkinje cells appeared normal in Alpk1 -/- mice. Transgenic expression of full-length Alpk1 rescued motor coordination deficits in Alpk1 -/- mutant mice.
In 16 affected individuals from 5 unrelated families (3 from the United States, 1 from the Netherlands, and 1 from Italy) with retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (ROSAH; 614979), Williams et al. (2019) identified heterozygosity for a c.710C-T transition (c.710C-T, NM_025144) in exon 9 of the ALPK1 gene, resulting in a thr237-to-met (T237M) substitution at a highly conserved residue. The mutation segregated fully with disease in the families, and was not found in the gnomAD database. The occurrence of the same c.710C-T transition within a CG dimer in all 5 families was consistent with the existence of a mutational hotspot. Patient fibroblasts showed significantly fewer ciliated cells than control fibroblasts. In addition, HeLa cells transfected with the T237M mutant showed significantly higher numbers of multinucleated cells than controls.
In 2 unrelated Chinese girls with ROSAH syndrome, Zhong et al. (2020) identified heterozygosity for the recurrent T237M mutation in the ALPK1 gene. The mutation arose de novo in both probands.
Kozycki et al. (2022) identified heterozygosity for the T237M mutation in ALPK1 in 20 patients with ROSAH syndrome from 12 unrelated families.
In a patient (patient 13.1) with retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (ROSAH; 614979), Kozycki et al. (2022) identified heterozygosity for a c.761A-G transition (c.761A-G, NM_025144.4) in the ALPK1 gene resulting in a tyr254-to-cys (Y254C) substitution in the ligand-binding domain of the protein. The mutation, which was identified by whole-exome sequencing, was absent from the gnomAD database and the patient's mother; DNA was not available from the deceased father.
Chen, M., Xu, R. Motor coordination deficits in Alpk1 mutant mice with the inserted piggyBac transposon. BMC Neurosci. 12: 1, 2011. [PubMed: 21208416] [Full Text: https://doi.org/10.1186/1471-2202-12-1]
Kozycki, C. T., Kodati, S., Huryn, L., Wang, H., Warner, B. M., Jani, P., Hammoud, D., Abu-Asab, M. S., Jittayasothorn, Y., Mattapallil, M. J., Tsai, W. L., Ullah, E., and 59 others. Gain-of-function mutations in ALPK1 cause an NF-kappaB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome. Ann. Rheum. Dis. 81: 1453-1464, 2022. [PubMed: 35868845] [Full Text: https://doi.org/10.1136/annrheumdis-2022-222629]
Middelbeek, J., Clark, K., Venselaar, H., Huynen, M. A., van Leeuwen, F. N. The alpha-kinase family: an exceptional branch on the protein kinase tree. Cell. Molec. Life Sci. 67: 875-890, 2010. [PubMed: 20012461] [Full Text: https://doi.org/10.1007/s00018-009-0215-z]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 143-150, 2000. [PubMed: 10819331] [Full Text: https://doi.org/10.1093/dnares/7.2.143]
Rashid, M., van der Horst, M., Mentzel, T., Butera, F., Ferreira, I., Pance, A., Rutten, A., Luzar, B., Marusic, Z., de Saint Aubain, N., Ko, J. S., Billings, S. D., and 14 others. ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma. Nature Commun. 10: 2213, 2019. Note: Electronic Article. [PubMed: 31101826] [Full Text: https://doi.org/10.1038/s41467-019-09979-0]
Ryazanov, A. G., Pavur, K. S., Dorovkov, M. V. Alpha-kinases: a new class of protein kinases with a novel catalytic domain. Curr. Biol. 9: R43-R45, 1999. [PubMed: 10021370] [Full Text: https://doi.org/10.1016/s0960-9822(99)80006-2]
Williams, L. B., Javed, A., Sabri, A., Morgan, D. J., Huff, C. D., Grigg, J. R., Heng, X. T., Khng, A. J., Hollink, I. H. I. M., Morrison, M. A., Owen, L. A., Anderson, K., and 29 others. ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. Genet. Med. 21: 2103-2115, 2019. [PubMed: 30967659] [Full Text: https://doi.org/10.1038/s41436-019-0476-3]
Zhong, L., Wang, J., Wang, W., Wang, L., Quan, M., Tang, X., Gou, L., Wei, M., Xiao, J., Zhang, T., Sui, R., Zhou, Q., Song, H. Juvenile onset splenomegaly and oculopathy due to germline mutation in ALPK1. J. Clin. Immun. 40: 350-358, 2020. [PubMed: 31939038] [Full Text: https://doi.org/10.1007/s10875-020-00741-6]
Zhou, P., She, Y., Dong, N., Li, P., He, H., Borio, A., Wu, Q., Lu, S., Ding, X., Cao, Y., Xu, Y., Gao, W., Dong, M., Ding, J., Wang, D.-C., Zamyatina, A., Shao, F. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature 561: 122-126, 2018. [PubMed: 30111836] [Full Text: https://doi.org/10.1038/s41586-018-0433-3]