Alternative titles; symbols
HGNC Approved Gene Symbol: WDR11
Cytogenetic location: 10q26.12 Genomic coordinates (GRCh38) : 10:120,851,362-120,909,524 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q26.12 | Hypogonadotropic hypogonadism 14 with or without anosmia | 614858 | Autosomal dominant | 3 |
| Intellectual developmental disorder, autosomal recessive 78 | 620237 | Autosomal recessive | 3 |
WDR11 is a member of the WD repeat-containing protein family. For background information on this family, see 604734.
Allelic deletions in 10q25-q26 and 19q13.3-q13.4 are common genetic alterations in glial tumors. Chernova et al. (2001) identified a balanced t(10;19) reciprocal translocation in a glioblastoma cell line that involved both critical regions on chromosomes 10 and 19. By positional cloning of the translocation breakpoint, they identified a novel WD-repeat gene on chromosome 10, which they designated WDR11. WDR11 encodes a deduced 1,224-amino acid polypeptide with a calculated molecular mass of 137 kD. It contains 6 putative WD40 repeats, a predicted transmembrane region, and a tyrosine kinase phosphorylation site. Northern blot analysis detected ubiquitous expression of 3 major transcripts (4.5, 2.7 and 2.0 kb) in all tissues tested. Chernova et al. (2001) determined that the translocation resulted in deletion of exon 5 and fusion of intron 4 of WDR11 to the 3-prime untranslated region of ZNF320 (606427), a novel member of the Kruppel-like zinc finger gene family on chromosome 19. Since ZNF320 is oriented toward the centromere of chromosome 19, both genes appeared on the same derivative chromosome, der(10). The chimeric transcript encodes an aberrant WDR11 polypeptide, which is truncated after the second of the 6 WD repeats. Because of the localization of WDR11 in a region frequently showing loss of heterozygosity in glioblastoma (see DMBT1; 601969) and because WDR11 is inactivated in glioblastoma cells, Chernova et al. (2001) considered WDR11 to be a candidate tumor suppressor gene involved in tumorigenesis of glial and other tumors.
To investigate developmental expression of Wdr11, Kim et al. (2010) performed whole-mount in situ hybridization analysis in mouse embryos from days E10.5 to E14.5. As early as E10.5, the entire developing central nervous system, except for the spinal cord, revealed Wdr11 expression. The neuroepithelium, including the diencephalic region that gives rise to hypothalamic neurons where GnRH (152760) neurons reside, stained strongly for Wdr11 at E11.5 and E12.5. At E14.5, high levels of Wdr11 expression were particularly noteworthy in the developing cortex and olfactory bulb. In the adult brain, intense Wdr11 expression was restricted to the olfactory bulb, the olfaction-related piriform cortex, the granule cell layer of the cerebellum, and neurons of the hippocampal formation. Kim et al. (2010) noted that the pattern of expression was consistent with a role for WDR11 in both normosmic and anosmic forms of hypogonadotropic hypogonadism.
Through immunofluorescent staining of control fibroblasts, Haag et al. (2021) showed juxtanuclear localization of WDR11; WDR11 was also detected in the trans-Golgi network.
Chernova et al. (2001) determined that the WDR11 gene contains 29 exons distributed over 58 kb and is oriented towards the telomere.
By positional cloning, Chernova et al. (2001) mapped the WDR11 gene to chromosome 10q26.
Using a yeast 2-hybrid screen, Kim et al. (2010) identified EMX1 (600034) as a WDR11 binding partner. The interaction was confirmed in mammalian cells by coimmunoprecipitation assays and further confirmed by GST pull-down analysis. Kim et al. (2010) generated WDR11 deletion mutants and performed GST pull-down assays to assess binding, which demonstrated that both the N terminus and the central portion of WDR11 bind to EMX1, whereas the C terminus does not. Immunostaining in a physiologically relevant human cell system consisting of immortalized human embryonic olfactory GnRH neuroblasts isolated from olfactory epithelium of an 8- to 12-week-old human embryo (FCNB4-hTERT cells) localized WDR11 to the cytoplasm. Fluorescence microscopy of transfected U2OS cells also showed a cytoplasmic localization for WDR11, whereas EMX1 localized to the nucleus. However, after treatment with leptomycin B, an inhibitor of nuclear export, both EMX1 and WDR11 colocalized in the nucleus, suggesting that WDR11 might be shuttling between nucleus and cytoplasm.
Hypogonadotropic Hypogonadism 14
Kim et al. (2010) screened 201 normosmic and hyposmic/anosmic patients with hypogonadotropic hypogonadism (HH14; 614858) for mutations in the candidate gene WDR11 (606417) and identified 5 different heterozygous missense mutations in 6 unrelated probands, including 5 normosmic patients (see, e.g., 606417.0001 and 606417.0002) and 1 anosmic patient (606417.0003). DNA from the parents was unavailable, but the mutations were not found in more than 400 controls.
Autosomal Recessive Intellectual Developmental Disorder 78
In 6 patients from 3 unrelated families with autosomal recessive intellectual developmental disorder-78 (MRT78; 620237), Haag et al. (2021) identified homozygous or compound heterozygous loss-of-function mutations in the WDR11 gene (606417.0004-606417.0007). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all 3 families. Western blot analysis of fibroblasts from 1 of the patients demonstrated complete absence of the WDR11 protein. Functional studies of the variants were not performed.
In a man with incomplete hypogonadotropic hypogonadism and an unrelated woman with complete HH, both of whom were normosmic (HH14; 614858), Kim et al. (2010) identified heterozygosity for a 3450T-G transversion in exon 28 of the WDR11 gene, resulting in a phe1150-to-leu (F1150L) substitution at a highly conserved residue near the C terminus. The mutation was not found in 420 white controls. Haplotype analysis indicated a shared haplotype around WDR11, suggesting that the 2 patients were likely to be descended from a recent common ancestor.
In a Turkish man with complete hypogonadotropic hypogonadism, who had bilateral cryptorchidism and a normal sense of smell (HH14; 614858), Kim et al. (2010) identified heterozygosity for a 1303G-A transition in exon 10 of the WDR11 gene, resulting in an ala435-to-thr (A435T) substitution at a highly conserved residue within the sixth WD domain. Transfection studies in HEK293 cells demonstrated that the A435T mutation abolishes EMX1 (600034) binding. The mutation was not found in 402 Turkish controls or 426 white controls.
In a man with anosmic hypogonadotropic hypogonadism (HH14; 614858), Kim et al. (2010) identified heterozygosity for a 2070T-A transversion in exon 16 of the WDR11 gene, resulting in a his690-to-gln (H690Q) substitution at a highly conserved residue within the ninth WD domain. Transfection studies in HEK293 cells demonstrated that the H690Q mutation abolishes EMX1 (600034) binding. The mutation was not found in 420 white controls.
In 2 sisters, born of consanguineous Syrian parents (family A), with autosomal recessive intellectual developmental disorder-78 (MRT78; 620237), Haag et al. (2021) identified a homozygous c.1255C-T transition (c.1255C-T, NM_018117.12) in exon 9 of the WDR11 gene, resulting in a gln419-to-ter (Q419X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Western blot analysis of patient fibroblasts showed complete absence of the WDR11 protein without indication of a truncated variant. The loss of WDR11 expression was also demonstrated through immunofluorescent studies of patient fibroblasts.
In a 12.5-year-old boy, born of unrelated parents from Singapore (family B), with autosomal recessive intellectual developmental disorder-78 (MRT78; 620237), Haag et al. (2021) identified compound heterozygous frameshift mutations in the WDR11 gene: a 4-bp deletion (c.3033_3036del, NM_018117.12) in exon 25 inherited from the unaffected mother and resulting in premature termination (Asp1011GlufsTer21), and 1-bp deletion (c.1439del; 606417.0006) in exon 10 inherited from the unaffected father, also resulting in premature termination (Asn480ThrfsTer32). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were found at low frequencies in the gnomAD database (1 of 251,436 alleles for the maternal mutation and 4 of 251,334 alleles for the paternal mutation). Based on the location of the mutations, both were predicted to result in nonsense-mediated mRNA decay and a complete loss of function. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the 1-bp deletion (c.1439del, NM_018117.12) in exon 10 of the WDR11 gene, resulting in a frameshift and premature termination (Asn480ThrfsTer32), that was found in compound heterozygous state in a patient with autosomal recessive intellectual developmental disorder-78 (MRT78; 620237) by Haag et al. (2021), see 606417.0005.
In 3 sibs, born of consanguineous Kuwaiti parents (family C), with autosomal recessive intellectual developmental disorder-78 (MRT78; 620237), Haag et al. (2021) identified a homozygous G-to-A transition in intron 23 of the WDR11 gene (c.2931+1G-A, NM_018117.12), predicted to result in a splicing defect, the skipping of exon 23, a frameshift, and premature termination. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found once in the gnomAD database (1 of 251,298 alleles). Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a complete loss of function.
Chernova, O. B., Hunyadi, A., Malaj, E., Pan, H., Crooks, C., Roe, B., Cowell, J. K. A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells. Oncogene 20: 5378-5392, 2001. [PubMed: 11536051] [Full Text: https://doi.org/10.1038/sj.onc.1204694]
Haag, N., Tan, E.-C., Begemann, M., Buschmann, L., Kraft, F., Holschbach, P., Lai, A. H. M., Brett, M., Mochida, G. H., DiTroia, S., Pais, L., Neil, J. E., Al-Saffar, M., Bastaki, L., Walsh, C. A., Kurth, I., Knopp, C. Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability. Europ. J. Hum. Genet. 29: 1663-1668, 2021. [PubMed: 34413497] [Full Text: https://doi.org/10.1038/s41431-021-00943-5]
Kim, H.-G., Ahn, J.-W., Kurth, I., Ullmann, R., Kim, H.-T., Kulharya, A., Ha, K.-S., Itokawa, Y., Meliciani, I., Wenzel, W., Lee, D., Rosenberger, G., and 12 others. WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am. J. Hum. Genet. 87: 465-479, 2010. [PubMed: 20887964] [Full Text: https://doi.org/10.1016/j.ajhg.2010.08.018]