Alternative titles; symbols
HGNC Approved Gene Symbol: WDR45B
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38) : 17:82,614,562-82,648,444 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures | 617977 | Autosomal recessive | 3 |
WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins, such as WDR45B, have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids (Proikas-Cezanne et al., 2004).
By searching a genomic database for sequences similar to WIPI1 (609224), followed by RT-PCR of normal testis mRNA, Proikas-Cezanne et al. (2004) cloned WDR45B, which they called WIPI3. The deduced protein contains 7 WD-like repeats. Northern blot analysis detected ubiquitous expression of an approximately 3.0-kb transcript. Highest expression was in heart, skeletal muscle, and pancreas. Proikas-Cezanne et al. (2004) also found that WIPI3 expression was upregulated in a significant portion of ovarian and uterine cancers.
By genomic sequence analysis, Proikas-Cezanne et al. (2004) mapped the WDR45B gene to chromosome 17q25.3.
In 6 patients from 3 unrelated consanguineous families with neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures (NEDSBAS; 617977), Suleiman et al. (2018) identified homozygous nonsense mutations in the WDR45B gene (R225X, 609226.0001 and Q267X, 609226.0002). The mutations, which were found by whole-exome sequencing or screening of a neurology gene panel, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a complete loss of function.
Suleiman et al. (2018) stated that Anazi et al. (2017) had identified a homozygous R225X mutation in the WDR45B gene in an unrelated child (patient 15DG1306) with global developmental delay and microcephaly and that Najmabadi et al. (2011) had identified a homozygous missense variant in the WDR45B gene (R109Q) in 3 members of a consanguineous family (family 8500320) with intellectual disability and microcephaly. Additional details were not provided and no functional studies of those variants were performed. The study by Anazi et al. (2017) included a cohort of 337 patients with intellectual disability (documented IQ of 70 or less) who underwent genetic studies, including molecular karyotyping, analysis of a multigene panel, and whole-exome sequencing. The study by Najmabadi et al. (2011) included homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability.
In 3 patients from 2 unrelated consanguineous families (families 2 and 3) with neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures (NEDSBAS; 617977), Suleiman et al. (2018) identified a homozygous c.673C-T transition (c.673C-T, NM_019613.3) in the WDR45B gene, resulting in an arg225-to-ter (R225X) substitution. The mutation, which was found by screening of a neurology gene panel, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a complete loss of function. Suleiman et al. (2018) stated that Anazi et al. (2017) had identified a homozygous R225X mutation in the WDR45B gene in an unrelated child (patient 15DG1306) with global developmental delay and microcephaly The patient reported by Anazi et al. (2017) was part of a cohort of 337 patients with intellectual disability (documented IQ of 70 or less) who underwent genetic studies, including molecular karyotyping, analysis of a multigene panel, and whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In 3 sibs, born of consanguineous parents (family 1), with neurodevelopmental disorder with spastic quadriplegia, brain abnormalities, and seizures (NEDSBAS; 617977), Suleiman et al. (2018) identified a homozygous c.799C-T transition (c.799C-T, NM_019613.3) in the WDR45B gene, resulting in a gln267-to-ter (Q267X) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a complete loss of function.
Anazi, S., Maddirevula, S., Faqeih, E., Alsedairy, H., Alzahrani, F., Shamseldin, H. E., Patel, N., Hashem, M., Ibrahim, N., Abdulwahab, F., Ewida, N., Alsaif, H. S., and 36 others. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Molec. Psychiat. 22: 615-624, 2017. [PubMed: 27431290] [Full Text: https://doi.org/10.1038/mp.2016.113]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
Proikas-Cezanne, T., Waddell, S., Gaugel, A., Frickey, T., Lupas, A., Nordheim, A. WIPI-1-alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23: 9314-9325, 2004. [PubMed: 15602573] [Full Text: https://doi.org/10.1038/sj.onc.1208331]
Suleiman, J., Allingham-Hawkins, D., Hashem, M., Shamseldin, H. E., Alkuraya, F. S., El-Hattab, A. W. WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: a consistent neurodevelopmental syndrome. Clin. Genet. 93: 360-364, 2018. [PubMed: 28503735] [Full Text: https://doi.org/10.1111/cge.13054]