Alternative titles; symbols
HGNC Approved Gene Symbol: WDR26
SNOMEDCT: 1177167002;
Cytogenetic location: 1q42.11-q42.12 Genomic coordinates (GRCh38) : 1:224,385,146-224,434,797 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q42.11-q42.12 | Skraban-Deardorff syndrome | 617616 | Autosomal dominant | 3 |
WDR26 is a scaffolding protein that interacts with several proteins, including G-beta (see 139380)-gamma (see 606981) proteins, AXIN1 (603816), and PLCB2 (604114), and regulates various signaling pathways (Sun et al., 2013; Goto et al., 2016).
By searching EST databases for G-beta-like proteins containing a WD40 consensus sequence, followed by PCR of a heart cDNA library, Zhu et al. (2004) cloned human WDR26. The predicted 514-amino acid protein has a calculated molecular mass of 58.6 kD. It contains a WD40 region with 5 WD40 repeats in tandem arrays. WDR26 is evolutionarily conserved from yeast to human. Northern blot analysis detected a 3.7-kb WDR26 transcript in most adult human tissues, with highest expression in skeletal muscle and heart. In human fetal tissues, expression was highest in skeletal muscle and brain, with lower expression in liver, lung, and heart. Fluorescence microscopy demonstrated cytoplasmic expression of WDR26 in transfected COS-7 cells.
Using reporter assays, Zhu et al. (2004) found that expression of WDR26 in COS-7 cells significantly reduced FOS (164810) serum response element activity and ELK1 (311040) transcriptional activity. They concluded that WDR26 may participate in MAP kinase (see 601158) signaling pathways.
Sun et al. (2011) showed that WDR26 bound G-beta-gamma in Jurkat human T cells stimulated by SDF1 (CXCL12; 600835). Knockdown of WDR26 via small interfering RNA selectively inhibited G-beta-gamma-dependent PLCB (see 607120) and PI3K (see 601232) activation and attenuated chemotaxis in Jurkat T cells in vitro and in mice. WDR26 function depended on its ability to bind G-beta-gamma. Additional experiments showed that WDR26 controlled the ability of the negative regulator RACK1 (GNB2L1; 176981) to bind G-beta-gamma and inhibit leukocyte migration. Sun et al. (2011) concluded that WDR26 is a G-beta-gamma-binding protein that is required for the efficacy of G-beta-gamma signaling and leukocyte migration.
Sun et al. (2013) showed that WDR26 bound PLCB2 and enhanced PLCB2 membrane translocation and activation by G-beta-gamma in human leukocytes.
Goto et al. (2016) showed that human WDR26 and AXIN1 controlled beta-catenin (CTNNB1; 116806) levels to negatively regulate expression of Wnt (see 606359) target genes. Binding of WDR26 and AXIN1 was necessary for ubiquitination of CTNNB1. Goto et al. (2016) concluded that WDR26 is an AXIN1 partner that functions in the canonical Wnt signaling pathway.
Zhu et al. (2004) determined that the WDR26 gene contains 14 exons and spans about 46 kb.
By genomic sequence analysis, Zhu et al. (2004) mapped the WDR26 gene to chromosome 1q42.13.
In 15 unrelated patients with Skraban-Deardorff syndrome (SKDEAS; 617616), Skraban et al. (2017) identified 15 different de novo heterozygous mutations in the WDR26 gene (see, e.g., 617424.0001-617424.0006). There were 5 frameshift, 5 nonsense, 1 splice site, and 4 missense mutations. Analysis of patient cells from 3 patients, including 2 with truncating mutations (617424.0002 and 617424.0004) and 1 with a missense mutation (D284N; 617424.0005), showed that the truncating mutations resulted in significantly decreased mRNA and protein levels and the missense mutation resulted in slightly decreased mRNA and protein levels, suggesting haploinsufficiency as the pathogenic mechanism. Further functional studies and studies of the other variants were not performed. Skraban et al. (2017) postulated that reduced expression of WDR26 may alter multiple signaling pathways and cellular mechanisms. The patients, all of whom were of European descent or from the United States, were ascertained from several different large patient cohorts and gene repository databases; all mutations were found by trio-based exome sequencing. The frequency of WDR26 mutations was about 1 in 2,000 for all exome analyses and about 1 in 1,500 for individuals with intellectual disability, suggesting that this disorder may not be uncommon.
In a 4-year-old girl (individual 1) with Skraban-Deardorff syndrome (SKDEAS; 617616), Skraban et al. (2017) identified a de novo heterozygous c.1276G-T transversion (c.1276G-T, NM_025160.6) in exon 8 of the WDR26 gene, resulting in a glu426-to-ter (E426X) substitution. The mutation was found by trio exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 34-year-old woman (individual 2) with Skraban-Deardorff syndrome (SKDEAS; 617616), Skraban et al. (2017) identified a de novo heterozygous 2-bp deletion (c.1161_1162del, NM_025160.6) in exon 8 of the WDR26 gene, resulting in a frameshift and premature termination (His389ProfsTer6). The mutation was found by trio exome sequencing. Analysis of patient cells showed a 69% reduction in mRNA, consistent with nonsense-mediated mRNA decay, and 75% lower levels of truncated protein compared to controls. The findings were most consistent with haploinsufficiency rather than a dominant-negative effect.
In a 3-year-old girl (individual 3) with Skraban-Deardorff syndrome (SKDEAS; 617616), Skraban et al. (2017) identified a de novo heterozygous 1-bp deletion (c.1457delT, NM_025160.6) in exon 10 of the WDR26 gene, resulting in a frameshift and premature termination (Val486GlufsTer9). The mutation was found by trio exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 3-year-old girl (individual 5) with Skraban-Deardorff syndrome (SKDEAS; 617616), Skraban et al. (2017) identified a de novo heterozygous 2-bp deletion (c.904_905delCA, NM_025160.6) in exon 6 of the WDR26 gene, resulting in a frameshift and premature termination (Gln302AspfsTer22). The mutation was found by trio exome sequencing. Analysis of patient cells showed a 73% reduction in mRNA, consistent with nonsense-mediated mRNA decay, and 70% lower levels of truncated protein compared to controls. The findings were most consistent with haploinsufficiency rather than a dominant-negative effect.
In a 2-year-old girl (individual 6) with Skraban-Deardorff syndrome (SKDEAS; 617616), Skraban et al. (2017) identified a de novo heterozygous c.850G-A transition (c.850G-A, NM_025160.6) in exon 5 of the WDR26 gene, resulting in an asp284-to-asn (D284N) substitution at a highly conserved residue that lies outside of the beta-propeller structure and may be involved in extrinsic interactions. The mutation was found by trio exome sequencing. Analysis of patient cells showed a mild decrease in mRNA (88%) and protein (85%) levels compared to controls. Additional functional studies of the variant were not performed, but it was predicted to disrupt protein function.
In a 14.5-year-old boy (individual 9) with Skraban-Deardorff syndrome (SKDEAS; 617616), Skraban et al. (2017) identified a de novo heterozygous c.762T-G transversion (c.762T-G, NM_025160.6) in exon 4 of the WDR26 gene, resulting in a ser254-to-arg (S254R) substitution at a highly conserved residue in the WD6 repeat at the edge of a beta-sheet. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to disrupt protein function.
Goto, T., Matsuzawa, J., Iemura, S., Natsume, T., Shibuya, H. WDR26 is a new partner of Axin1 in the canonical Wnt signaling pathway. FEBS Lett. 590: 1291-1303, 2016. [PubMed: 27098453] [Full Text: https://doi.org/10.1002/1873-3468.12180]
Skraban, C. M., Wells, C. F., Markose, P., Cho, M. T., Nesbitt, A. I., Au, P. Y. B., Begtrup, A., Bernat, J. A., Bird, L. M., Cao, K., de Brouwer, A. P. M., Denenberg, E. H., and 28 others. WDR26 haploinsufficiency causes a recognizable syndrome of intellectual disability, seizures, abnormal gait, and distinctive facial features. Am. J. Hum. Genet. 101: 139-148, 2017. [PubMed: 28686853] [Full Text: https://doi.org/10.1016/j.ajhg.2017.06.002]
Sun, Z., Smrcka, A. V., Chen, S. WDR26 functions as a scaffolding protein to promote G-beta-gamma-mediated phospholipase C beta-2 (PLC-beta-2) activation in leukocytes. J. Biol. Chem. 288: 16715-16725, 2013. [PubMed: 23625927] [Full Text: https://doi.org/10.1074/jbc.M113.462564]
Sun, Z., Tang, X., Lin, F., Chen, S. The WD40 repeat protein WDR26 binds G-beta-gamma and promotes G-beta-gamma-dependent signal transduction and leukocyte migration. J. Biol. Chem. 286: 43902-43912, 2011. [PubMed: 22065575] [Full Text: https://doi.org/10.1074/jbc.M111.301382]
Zhu, Y., Wang, Y., Xia, C., Li, D., Li, Y., Zeng, W., Yuan, W., Liu, H., Zhu, C., Wu, X., Liu, M. WDR26: a novel G-beta-like protein, suppresses MAPK signaling pathway. J. Cell. Biochem. 93: 579-587, 2004. [PubMed: 15378603] [Full Text: https://doi.org/10.1002/jcb.20175]