HGNC Approved Gene Symbol: WBP2
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38): 17:75,845,699-75,856,436 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.1 | Deafness, autosomal recessive 107 | 617639 | Autosomal recessive | 3 |
WBP2 encodes WW domain-binding protein-2, which acts as a transcriptional coactivator for estrogen receptor-alpha (ESR1; 133430) and progesterone receptor (PGR; 607311) (summary by Buniello et al., 2016).
Using a functional screen of a mouse cDNA expression library, Chen and Sudol (1995) cloned 2 ligands, which they designated Wbp1 (606961) and Wpb2, that bound to the WW domain of human Yes kinase-associated protein (YAP; 606608). The globular WW domain, which is composed of 38 to 40 semiconserved amino acids, is involved in mediating protein-protein interactions through the binding of polyproline ligands. Thus, its function is similar to that of the Src homology-3 (SH3) domain. Sequence comparison showed no homology between the 2 Wpb2 proteins except in a short proline-rich region containing the invariant residues PPPPY, which the authors designated the PY motif. Wbp1 contains a single PY motif, whereas Wbp2 contains 2 in the forward orientation and 1 in the reverse orientation. A structural similarity between the WW and SH3 domains is a hydrophobic core of conserved aromatic residues surrounded by beta loops containing charged amino acids. Northern blot analysis of multiple human tissues revealed ubiquitous expression of a 2.0-kb WBP2 transcript.
Using the partial mouse cDNA as probe, Chen et al. (1997) cloned WBP2 from a human lung fibroblast cDNA library. The cDNA encodes a deduced 268-amino acid protein that shares 94% sequence identity with the mouse protein.
Buniello et al. (2016) stated that there are 10 protein-coding variants of human WBP2 and only 2 isoforms in the mouse homolog. The authors found that both mouse isoforms are present in brain and the inner ear, with the longer isoform, which contains exon 5, much more abundant in the inner ear, and the shorter isoform, which lacks exon 5, much more abundant in brain.
Since Wbp1 contains only a single PY motif, Chen and Sudol (1995) used this as a model protein to characterize interaction between the PY and WW domains. By mutagenesis followed by Western ligand blot analysis, they established that all residues of the PY motif engage in binding the WW domain, and that P2, P3, and Y5 are crucial but not entirely sufficient for optimal binding. Chen et al. (1997) confirmed and refined the consensus PY motif as XPPXW.
By FISH, Chen et al. (1997) mapped the WBP2 gene to chromosome 17q25.
Using targeted next-generation sequencing to screen 8,087 probands with deafness and 1,823 unaffected controls in China, Buniello et al. (2016) identified 2 probands with autosomal recessive deafness-107 (DFNB107; 617639) who had compound heterozygous missense mutations in the WBP2 gene (606962.0001-606062.0003). The parents in each family were heterozygous for one of the mutations.
Buniello et al. (2016) performed a high-throughput screen for hearing impairment using auditory brainstem responses (ABR) in Wbp2-deficient mice. At P14, ABR thresholds were comparable to those in littermate controls. Loss of sensitivity to frequencies of 24 kHz and above was apparent by 4 weeks, and became more evident at 14 and 28 weeks, spreading to lower frequencies by 44 weeks. Buniello et al. (2016) demonstrated that the hearing loss was associated with reduced expression of Esr1, Esr2 (601663), and Pgr in the cochlea and disruption of expression of key postsynaptic proteins. Wbp2 mutants were fertile and showed no other abnormalities.
In 2 unrelated Chinese children, a 5-year-old boy and a 9-year-old girl, with autosomal recessive deafness (DFNB107; 617639), Buniello et al. (2016) identified compound heterozygous missense mutations in the WBP2 gene. Both children had a c.478G-A transition (rs202022024) in exon 5, resulting in an ala160-to-thr (A160T) substitution. The boy also had a c.671C-T transition in exon 7, resulting in an ala224-to-val (A224V) substitution (606962.0002); the girl also had a c.487A-C transversion in exon 5, resulting in a met163-to-leu (M163L) substitution (606962.0003). Ala160 and ala224 are well-conserved residues across species, whereas met163 has an average conservation score. Of the 10 known protein-coding variants of WBP2, the ala160 and met163 residues are in all but one (transcript 3), and the ala224 residue is in 7 splice variants, but not in transcripts 9, 10, or 11.
For discussion of the c.671C-T transition in the WBP2 gene, resulting in an ala224-to-val (A224V) substitution, that was found in compound heterozygous state in a boy with autosomal recessive deafness-107 (DFNB107; 617639) by Buniello et al. (2016), see 606962.0001.
For discussion of the c.487A-C transversion in the WBP2 gene, resulting in a met163-to-leu (M163L), that was found in compound heterozygous state in a girl with autosomal recessive deafness-107 (DFNB107; 617639) by Buniello et al. (2016), see 606962.0001.
Buniello, A., Ingham, N. J. Lewis, M. A., Huma, S. C., Martinez-Vega, R., Varela-Nieto, I., Vizcay-Barrena, G., Fleck, R. A., Houston, O., Bardhan, T., Johnson, S. L., White, J. K., Yuan, H., Marcotti, W., Steel, K. P. Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing. EMBO Molec. Med. 8: 191-207, 2016. [PubMed: 26881968] [Full Text: https://doi.org/10.15252/emmm.201505523]
Chen, H. I., Einbond, A., Kwak, S.-J., Linn, H., Koepf, E., Peterson, S., Kelly, J. W., Sudol, M. Characterization of the WW domain of human Yes-associated protein and its polyproline containing ligands. J. Biol. Chem. 272: 17070-17077, 1997. [PubMed: 9202023] [Full Text: https://doi.org/10.1074/jbc.272.27.17070]
Chen, H. I., Sudol, M. The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules. Proc. Nat. Acad. Sci. 92: 7819-7823, 1995. [PubMed: 7644498] [Full Text: https://doi.org/10.1073/pnas.92.17.7819]