HGNC Approved Gene Symbol: WDR72
Cytogenetic location: 15q21.3 Genomic coordinates (GRCh38) : 15:53,513,741-53,762,878 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.3 | Amelogenesis imperfecta, type IIA3 | 613211 | Autosomal recessive | 3 |
WDR72 has a predicted structure characteristic of proteins that mediate membrane deformation. It plays an important role in enamel mineralization, possibly due to endocytic vesicle trafficking (Katsura et al., 2014).
By searching for genes in a region of chromosome 15 associated with amelogenesis imperfecta, El-Sayed et al. (2009) identified the WDR72 gene. The deduced 1,102-amino acid protein contains 7 WD40 domains, which are predicted to form the blades of a 7 beta-propeller structure and function as a docking platform for protein-protein interactions. WDR72 shares highest similarity with WDR7, which is involved in vesicle mobilization and Ca(2+)-dependent exocytosis at synapses. Database analysis suggested WDR72 is expressed in a wide variety of tissues. Immunohistochemical analysis of developing mouse incisors detected Wdr72 expression in the enamel organ, with more intense staining in maturation ameloblasts than in secretory ameloblasts. Wdr72 was also detected in some bone and connective tissue cells.
Transient expression of WDR72 fused to green fluorescent protein (GFP) in HEK293T cells showed that WDR72 localized to the cytoplasm (Lee et al., 2010).
By molecular modeling, Katsura et al. (2014) determined that full-length human WDR72 contains two 7-bladed beta-propellers formed by 2 clusters of WD40 repeat domains at its N terminus, followed by a C-terminal alpha-solenoid tail. The authors noted that this domain organization is characteristic of vesicle coat proteins that mediate membrane deformation. Quantitative real-time PCR and Western blot analysis revealed that Wdr72 expression increased in mouse ameloblasts from secretory to maturation stages. In mature mouse ameloblasts, Wdr72 showed a vesicle-like punctate localization.
El-Sayed et al. (2009) determined that the WDR72 gene contains 19 exons and spans about 250 kb.
Katsura et al. (2014) reported that WDR72 has 20 exons. Exon 1 is noncoding.
The WDR72 gene maps to chromosome 15q21.3 (El-Sayed et al., 2009).
In a large Pakistani family segregating autosomal recessive hypomaturation amelogenesis imperfecta (AI) mapping to chromosome 15q21.3 (AI2A3; 613211), El-Sayed et al. (2009) identified a homozygous nonsense mutation in the WDR72 gene (613214.0001). Analysis of the WDR72 gene in 4 Pakistani AI families and 5 Omani AI families revealed homozygosity for the same mutation in another Pakistani AI family with a similar clinical phenotype; in addition, 2 different WDR72 mutations were found in 2 Omani AI families (613214.0002 and 613214.0003, respectively). The mutations all cosegregated consistently with the phenotype and were not found in controls.
By whole-exome sequencing of the WDR72 gene in a Mexican and a Turkish family segregating autosomal recessive amelogenesis imperfecta, Lee et al. (2010) identified the same homozygous 2-bp deletion (c.1467_1468delAT; 613214.0004) that segregated with the disorder in both families.
Katsura et al. (2014) found that Wdr72 -/- mice appeared healthy, with no obvious tissue or tooth phenotype, except for a defect in enamel maturation. At weaning on postnatal day 21, Wdr72 -/- mice showed reduced body weight, likely due to difficulty chewing hard foods. Incisors and molar crowns showed loss of enamel at occlusal surfaces, while the exposed dentin remained relatively intact. Wdr72 -/- mandibles showed hypomineralized enamel at the onset of the maturation stage, with retained proteins in the enamel matrix, shortened ameloblast height, and reduced expression of the H+/Cl- exchanger Clc5 (300008) in early endosomes. Wdr72 -/- ameloblasts showed reduced amelogenin (AMELX; 300391) immunoreactivity, suggesting defects in resorption of amelogenin fragments from the matrix during enamel maturation.
In affected members of 2 unrelated Pakistani families segregating autosomal recessive hypomaturation-type amelogenesis imperfecta (AI2A3; 613211), El-Sayed et al. (2009) identified homozygosity for a 2348C-G transversion in exon 15 of the WDR72 gene, predicted to result in a ser783-to-ter (S783X) substitution. The mutation was not found in 192 Pakistani controls.
In the proband of a consanguineous Omani family with hypomaturation-type amelogenesis imperfecta (AI2A3; 613211), El-Sayed et al. (2009) identified homozygosity for a 2934G-A transition in exon 17 of the WDR72 gene, resulting in a trp978-to-ter (W978X) substitution. The mutation was not found in 192 controls of differing ethnic origins.
In a brother and sister from a consanguineous Omani family with hypomaturation-type amelogenesis imperfecta (AI2A3; 613211), El-Sayed et al. (2009) identified homozygosity for a 1-bp deletion (2857delA) in exon 16 of the WDR72 gene, resulting in a terminal frameshift. The mutation was not found in 192 controls of differing ethnic origins.
By whole-exome sequencing of the WDR72 gene in a Mexican and a Turkish family segregating autosomal recessive amelogenesis imperfecta (AI2A3; 613211), Lee et al. (2010) identified the same homozygous 2-bp deletion (c.1467_1468delAT; 613214.0004) in exon 12 that segregated with the disorder in both families. The deletion was predicted to cause a frameshift and premature termination (Val491fsTer497). The permanent dentition of the 3 affected sisters from the Mexican family (family 1) showed enamel roughness and discoloration. Deterioration of the dentition was particularly evident on the occlusal or incisal half of the tooth. The enamel layer showed reduced radiodensity. The phenotype in the 2 affected brothers in the Turkish family (family 2) was more mild than that in the Mexican sisters but had the same reduced radiodensity of the enamel layer.
El-Sayed, W., Parry, D. A., Shore, R. C., Ahmed, M., Jafri, H., Rashid, Y., Al-Bahlani, S., Al Harasi, S., Kirkham, J., Inglehearn, C. F., Mighell, A. J. Mutations in the beta propeller WDR72 cause autosomal-recessive hypomaturation amelogenesis imperfecta. Am. J. Hum. Genet. 85: 699-705, 2009. [PubMed: 19853237] [Full Text: https://doi.org/10.1016/j.ajhg.2009.09.014]
Katsura, K. A., Horst, J. A., Chandra, D., Le, T. Q., Nakano, Y., Zhang, Y., Horst, O. V., Zhu, L., Le, M. H., DenBesten, P. K. WDR72 models of structure and function: a stage-specific regulator of enamel mineralization. Matrix Biol. 38: 48-58, 2014. [PubMed: 25008349] [Full Text: https://doi.org/10.1016/j.matbio.2014.06.005]
Lee, S.-K., Seymen, F., Lee, K.-E., Kang, H.-Y., Yildirim, M., Tuna, E. B., Gencay, K., Hwang, Y.-H., Nam, K. H., De La Garza, R. J., Hu, J. C.-C., Simmer, J. P., Kim, J.-W. Novel WDR72 mutation and cytoplasmic localization. J. Dent. Res. 89: 1378-1382, 2010. [PubMed: 20938048] [Full Text: https://doi.org/10.1177/0022034510382117]