Alternative titles; symbols
HGNC Approved Gene Symbol: WDR81
Cytogenetic location: 17p13.3 Genomic coordinates (GRCh38): 17:1,716,523-1,738,585 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.3 | Cerebellar ataxia, impaired intellectual development, and dysquilibrium syndrome 2 | 610185 | Autosomal recessive | 3 |
| Hydrocephalus, congenital, 3, with brain anomalies | 617967 | Autosomal recessive | 3 |
Conversion of early to late endosomes is marked by decreased membrane content of phosphatidylinositol 3-phosphate (PtdIns3P) and appearance of RAB7 (602298). WDR81 interacts with WDR91 (616303) in an endosomal protein complex that inhibits PtdIns3 kinase (PI3K; see 171834), permitting loss of PtdIns3P and conversion of early to late endosomes (Liu et al., 2016).
Okazaki et al. (2004) cloned mouse Wdr81, which they designated FLJ00182. The deduced protein contains 693 amino acids.
Gulsuner et al. (2011) stated that the longest isoform of the human WDR81 gene, isoform-1, contains 1,941 amino acids. The protein contains an N-terminal BEACH (Beige and Chediak-Higashi) domain, a MFS (major facilitator superfamily) domain, and 6 C-terminal WD40 repeats. The protein is predicted to be a transmembrane protein with 6 membrane-spanning domains. Human WDR81 was expressed in all brain regions analyzed, with highest levels of expression in the cerebellum and corpus callosum. Wdr81 was detected in Purkinje cells in the cerebellum of mouse embryos, and was coexpressed with genes involved in neuronal differentiation and projection, axonogenesis, and cell morphogenesis, suggesting a role in development.
Traka et al. (2013) stated that mouse Wdr81 isoform-1, which is orthologous to human isoform-1, contains 1,934 amino acids and has a calculated molecular mass of approximately 211 kD. RT-PCR detected variable Wdr81 expression in all 11 mouse tissues examined. Western blot analysis detected Wdr81 isoforms of approximately 90 and 80 kD in mouse cerebellum, brain, and spinal cord, but not in thymus, suggesting that isoform-1 is not expressed in these tissues or undergoes proteolytic processing. Immunohistochemical analysis revealed Wdr81 expression in central nervous system neurons, including Purkinje cells and neurons of deep cerebellar nuclei, and in photoreceptor cells. Wdr81 localized to mitochondria.
Using immunohistochemical analysis, Liu et al. (2016) found that WDR81 partially colocalized with early endosomal protein EEA1 (605070) and late endosomal protein RAB7 in HeLa cells.
Gulsuner et al. (2011) stated that the human WDR81 gene contains 10 exons.
Hartz (2011) mapped the WDR81 gene to chromosome 17p13.3 based on an alignment of the WDR81 sequence (GenBank AK091136) with the genomic sequence (GRCh37).
Okazaki et al. (2004) mapped the mouse Wdr81 gene to chromosome 11.
Loss of vps18 (608551) in C. elegans macrophage-like coelomocytes causes severe defects in endosome/lysosome fusion. Liu et al. (2016) found that concomitant knockdown of sorf1 and sorf2, the orthologs of mammalian WDR91 and WDR81, respectively, partially rescued the endosome/lysosome fusion defects in vps18-knockout coelomocytes. Sorf1 and sorf2 formed a complex that interacted with the beclin-1 subunit (BECN1; 604378) of the PI3K complex. Deletion of sorf1 or sorf2 in vps18-positive coelomocytes caused endosome enlargement due to enriched beclin-1 on early endosomes and enhanced PI3K activity, resulting in prolonged existence of endosomal PtdIns3P and delayed conversion of early to late endosomes. Knockout of WDR91 or WDR81 in HeLa cells via CRISPR/Cas9 resulted in enlarged endosomes, impaired lysosome-mediated degradation of EGFR (131550), elevated endosomal EEA1, and BECN1-dependent elevation of endosomal PtdIns3P. Coimmunoprecipitation experiments revealed that epitope-tagged BECN1 interacted with epitope-tagged WDR91 and WDR81 in transfected HEK293 cells. In HeLa cells, WDR81 and WDR91 inhibited PI3K activity in a kinase assay. Liu et al. (2016) concluded that WDR81 and WDR91 are required for conversion of early to late endosomes.
Cerebellar Ataxia, Impaired Intellectual Development, and Dysequilibrium Syndrome 2
In affected members of a consanguineous Turkish family with autosomal recessive cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome-2 (CAMRQ2; 610185), Gulsuner et al. (2011) identified a homozygous mutation in the WDR81 gene (P856L; 614218.0001). Homozygosity for the mutation segregated with the phenotype. The mutation occurred in a highly conserved residue and was not found in 549 controls. The mutation was found by targeted sequencing of the candidate disease region identified by linkage analysis. The family had originally been reported by Turkmen et al. (2006) as having cerebellar hypoplasia, mental retardation, and an inability to walk bipedally, resulting in quadrupedal locomotion as a functional adaptation. Brain MRI of affected individuals by Gulsuner et al. (2011) showed morphologic abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural MRI showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and several Brodmann areas.
Alazami et al. (2015) identified a homozygous missense variant in the WDR81 gene (G282E) in a patient from a consanguineous family with CAMRQ2. Details of the family and segregation analysis were not provided. The proband was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the WDR81 variant were not performed.
In 2 sisters, born of consanguineous parents of Yemeni origin, with CAMRQ2, Komara et al. (2016) identified a homozygous truncating mutation in the WDR81 gene (R1333X; 614218.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Congenital Hydrocephalus 3 with Brain Anomalies
In 2 unrelated patients, each conceived of consanguineous Saudi parents (families 13 and 26), with autosomal recessive hydrocephalus-3 (HYC3; 617967), Shaheen et al. (2017) identified homozygous mutations in the WDR81 gene (Q1096X, 614218.0003 and G282E, 614218.0004). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Segregation of the disorder with the genotype was demonstrated for 1 family. Both families had histories of additional similarly affected pregnancies, but DNA from those patients was not available. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect. The patients were part of a large genetic study of 27 consanguineous Saudi families with congenital hydrocephalus.
Homozygous mice from the N-ethyl-N-nitrosourea-induced mutant line nur5 appear normal at birth, but they develop tremor and an abnormal gait as adults. Traka et al. (2013) found that Purkinje cells developed normally in nur5/nur5 animals before postnatal day 21, but that they began dying soon afterwards. Purkinje cell loss correlated with progressive ataxia in nur5/nur5 mice. Nur5/nur5 animals also developed noticeable shrinkage of the eye, concomitant with loss of photoreceptor cells and thinning of the retina. Traka et al. (2013) identified the nur5 mutation as a leu1349-to-pro (L1349P) substitution within the MFS domain of Wdr81. Quantitative RT-PCR detected expression of Wdr81 with L1349P at a level comparable to that of wildtype Wdr81 in cerebellum, and Wdr81 with L1349P localized normally to mitochondria. However, a significant subset of nur5/nur5 mitochondria were substantially larger and more spherical than wildtype mitochondria and showed disrupted cristae and outer membranes.
In affected members of a consanguineous Turkish family with autosomal recessive cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome-2 (CAMRQ2; 610185) (Turkmen et al., 2006), Gulsuner et al. (2011) identified a homozygous C-to-T transition at cDNA position 2567 (2567C-T) in exon 1 of the WDR81 gene, resulting in a pro856-to-leu (P856L) substitution in a highly conserved residue in the MFS domain of isoform-1. The mutation was not found in 549 controls.
In 2 sisters, born of consanguineous parents of Yemeni origin, with autosomal recessive cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome-2 (CAMRQ2; 610185), Komara et al. (2016) identified a homozygous c.3997C-T transition (c.3997C-T, NM_001163809.1) in exon 4 of the WDR81 gene, resulting in an arg1333-to-ter (R1333X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. One of the patients, who also had hearing loss, had a homozygous missense variant (R158W) in the LHFPL5 gene (609427), which is responsible for autosomal recessive deafness-67 (DFNB67; 610265).
In a patient, conceived of consanguineous Saudi parents (family 13), with congenital hydrocephalus-3 with brain anomalies (HYC3; 617967), Shaheen et al. (2017) identified a homozygous c.3286C-T transition (c.3286C-T, NM_001163809.1) in the WDR81 gene, resulting in a gln1096-to-ter (Q1096X) substitution. The mutation, which was found by exome sequencing of a 'neuro panel,' was confirmed by Sanger sequencing and segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In a patient, conceived of consanguineous Saudi parents (family 26), with congenital hydrocephalus-3 with brain anomalies (HYC3; 617967), Shaheen et al. (2017) identified a homozygous c.845G-A transition (c.845G-A, NM_001163809.1) in the WDR81 gene, resulting in a gly282-to-glu (G282E) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases or in 4,577 Saudi controls. DNA from the parents was not available for segregation analysis. Functional studies of the variant and studies of patient cells were not performed.
Alazami, A. M., Patel, N., Shamseldin, H. E., Anazi, S., Al-Dosari, M. S., Alzahrani, F., Hijazi, H., Alshammari, M., Aldahmesh, M. A., Salih, M. A., Faqeih, E., Alhashem, A., and 41 others. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10: 148-161, 2015. [PubMed: 25558065] [Full Text: https://doi.org/10.1016/j.celrep.2014.12.015]
Gulsuner, S., Tekinay, A. B., Doerschner, K., Boyaci, H., Bilguvar, K., Unal, H., Ors, A., Onat, O. E., Atalar, E., Basak, A. N., Topaloglu, H., Kansu, T., Tan, M., Tan, U., Gunel, M., Ozcelik, T. Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred. Genome Res. 21: 1995-2003, 2011. [PubMed: 21885617] [Full Text: https://doi.org/10.1101/gr.126110.111]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/8/2011.
Komara, M., John, A., Suleiman, J., Ali, B. R., Al-Gazali, L. Clinical and molecular delineation of dysequilibrium syndrome type 2 and profound sensorineural hearing loss in an inbred Arab family. Am. J. Med. Genet. 170A: 540-543, 2016. [PubMed: 26437881] [Full Text: https://doi.org/10.1002/ajmg.a.37421]
Liu, K., Jian, Y., Sun, X., Yang, C., Gao, Z., Zhang, Z., Liu, X., Li, Y., Xu, J., Jing, Y., Mitani, S., He, S., Yang, C. Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion. J. Cell Biol. 212: 181-198, 2016. Note: Erratum: J. Cell Biol. 212: 739 only, 2016. [PubMed: 26783301] [Full Text: https://doi.org/10.1083/jcb.201506081]
Okazaki, N., Kikuno, R., Ohara, R., Inamoto, S., Koseki, H., Hiraoka, S., Saga, Y., Kitamura, H., Nakagawa, T., Nagase, T., Ohara, O., Koga, H. Prediction of the coding sequences of mouse homologues of FLJ genes: the complete nucleotide sequences of 110 mouse FLJ-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries. DNA Res. 11: 127-135, 2004. [PubMed: 15449545] [Full Text: https://doi.org/10.1093/dnares/11.2.127]
Shaheen, R., Sebai, M. A., Patel, N., Ewida, N., Kurdi, W., Altweijri, I., Sogaty, S., Almardawi, E., Seidahmed, M. Z., Alnemri, A., Madirevula, S., Ibrahim, N., and 17 others. The genetic landscape of familial congenital hydrocephalus. Ann. Neurol. 81: 890-897, 2017. [PubMed: 28556411] [Full Text: https://doi.org/10.1002/ana.24964]
Traka, M., Millen, K. J., Collins, D., Elbaz, B., Kidd, G. J., Gomez, C. M., Popko, B. WDR81 is necessary for Purkinje and photoreceptor cell survival. J. Neurosci. 33: 6834-6844, 2013. [PubMed: 23595742] [Full Text: https://doi.org/10.1523/JNEUROSCI.2394-12.2013]
Turkmen, S., Demirhan, O., Hoffmann, K., Diers, A., Zimmer, C., Sperling, K., Mundlos, S. Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p. (Letter) J. Med. Genet. 43: 461-464, 2006. [PubMed: 16371500] [Full Text: https://doi.org/10.1136/jmg.2005.040030]