Alternative titles; symbols
HGNC Approved Gene Symbol: DKK2
Cytogenetic location: 4q25 Genomic coordinates (GRCh38): 4:106,921,802-107,036,313 (from NCBI)
For background information on WNT and Dickkopf proteins, see WNT6 (604663) and DKK1 (605189).
By searching EST databases with a partial DKK3 (605416) sequence, followed by probing a fetal lung cDNA library, Krupnik et al. (1999) isolated a cDNA encoding DKK2. The deduced 259-amino acid DKK2 protein, like DKK1, DKK3, and DKK4 (605417), possesses an N-terminal signal peptide and 2 conserved cysteine-rich domains, which are separated by a linker region and contain 10 cys residues each. The second cys region has a putative lipid-binding function that may facilitate WNT/DKK interactions at the plasma membrane. The linker region contains 50 to 55 amino acids in DKK1, DKK2, and DKK4, whereas in DKK3 it contains only 12 amino acids. All DKKs have several potential sites for cleavage by furin-type proteases. Northern blot analysis revealed expression of 4.0- and 4.5-kb DKK2 transcripts in heart, brain, skeletal muscle, and lung. Western blot analysis showed that DKK2 is secreted as a 15- to 17-kD protein. Functional analysis determined that DKK2 does not block Xenopus Wnt8 induction of a secondary axis in frog embryos.
Gross (2018) mapped the DKK2 gene to chromosome 4q25 based on an alignment of the DKK2 sequence (GenBank BC075078) with the genomic sequence (GRCh38).
Associations Pending Confirmation
Kalsi et al. (2010) conducted a systematic, gene-centric association study of alcohol dependence using 518 SNPs within the 65 genes of a linkage peak on chromosome 4q21-q32. Case-only regression analysis with the quantitative variable of alcohol-dependent symptoms was performed in 562 genetically independent cases of the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample. Gene-wise correction for multiple testing yielded empirical evidence of association with 3 SNPs in DKK2 in the cohort (rs427983, rs419558, rs399087; p less than 0.007). The association was replicated in 847 cases of European descent from a large independent sample, the Collaborative Study of the Genetics of Alcoholism (COGA). Haplotype-specific expression measurements in postmortem tissue samples suggested a functional role for DKK2.
Gross, M. B. Personal Communication. Baltimore, Md. 5/23/2018.
Kalsi, G., Kuo, P.-H., Aliev, F., Alexander, J., McMichael, O., Patterson, D. G., Walsh, D., Zhao, Z., Schuckit, M., Nurnberger, J., Jr., Edenberg, H., Kramer, J., Hesselbrock, V., Tischfield, J. A., Vladimirov, V., Prescott, C. A., Dick, D. M., Kendler, K. S., Riley, B. P. A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts. Hum. Molec. Genet. 19: 2497-2506, 2010. Note: Erratum: Hum. Molec. Genet. 19: 4121 only, 2010. [PubMed: 20332099] [Full Text: https://doi.org/10.1093/hmg/ddq112]
Krupnik, V. E., Sharp, J. D., Jiang, C., Robison, K., Chickering, T. W., Amaravadi, L., Brown, D. E., Guyot, D., Mays, G., Leiby, K., Chang, B., Duong, T., Goodearl, A. D. J., Gearing, D. P., Sokol, S. Y., McCarthy, S. A. Functional and structural diversity of the human Dickkopf gene family. Gene 238: 301-313, 1999. [PubMed: 10570958] [Full Text: https://doi.org/10.1016/s0378-1119(99)00365-0]