Alternative titles; symbols
HGNC Approved Gene Symbol: WDR45
SNOMEDCT: 732959007;
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38) : X:49,074,442-49,101,178 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Neurodegeneration with brain iron accumulation 5 | 300894 | X-linked dominant | 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 WIPI4, 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 WIPI4. The deduced protein contains 7 WD-like repeats. Northern blot analysis detected ubiquitous expression of an approximately 1.8-kb transcript. Highest expression was in heart and skeletal muscle. Proikas-Cezanne et al. (2004) also found that WIPI4 expression was downregulated in a significant portion of renal and pancreatic cancers.
By genomic sequence analysis, Proikas-Cezanne et al. (2004) mapped the WIPI4 gene to chromosome Xp11.23. They identified a putative WIPI4 pseudogene at chromosome 4q31.3.
The WDR45 gene has an important role in the autophagy pathway, which is the major intracellular degradation system by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (summary by Saitsu et al., 2013).
In 20 unrelated patients with neurodegeneration with brain iron accumulation-5 (NBIA5; 300894), Haack et al. (2012) identified 19 different de novo heterozygous or hemizygous mutations in the WDR45 gene (see, e.g., 300526.0001-300526.0002). Most of the mutations were truncating, but 2 were missense mutations affecting highly conserved residues. The mutations were located throughout the coding sequence. Initial mutations were identified by exome sequencing and all were confirmed by Sanger sequencing. Seventeen females and 3 males were affected, and the phenotype was similar in all. Since WDR45 is on the X chromosome, Haack et al. (2012) concluded that the males must be somatic mosaic for the mutation, which was demonstrated in 1 affected male. Presumably, males with germline WDR45 mutations are nonviable. Females may either harbor germline or somatic mutations, and several affected females had evidence of skewed X inactivation. These factors may contribute to disease manifestations.
Saitsu et al. (2013) identified 5 different de novo heterozygous truncating mutations in the WDR45 gene (see, e.g., 300526.0003-300526.0005) in 5 unrelated women with NBIA5. The initial mutations were identified by exome sequencing of 2 patients. Patients had delayed psychomotor development in infancy or early childhood that remained stable until young adulthood when all patients developed further severe motor and cognitive decline, with parkinsonism, dystonia, extrapyramidal signs, and dementia. Most became bedridden with an inability to care for themselves. Brain MRI showed iron accumulation in the globus pallidus and substantia nigra. Lymphoblastoid cells from 4 of the patients showed exclusive expression of the mutant transcript, suggesting X inactivation of the wildtype allele. All patient cells showed decreased levels of the mutant proteins, suggesting protein instability. Patient cells showed impaired autophagic flux. Immunofluorescence studies showed the accumulation of autophagic structures in patient cells, consistent with improper autophagosome formation. The findings suggested that impairment of autophagy contributes to the pathogenesis of this neurodegenerative disorder.
In 2 unrelated females with neurodegeneration with brain iron accumulation-5 (NBIA5; 300894), Haack et al. (2012) identified a de novo heterozygous 1-bp deletion at nucleotide 1007 of the WDR45 gene, resulting in a frameshift and premature termination (Tyr336CysfsTer5).
In a female with neurodegeneration with brain iron accumulation-5 (NBIA5; 300894), Haack et al. (2012) identified a de novo heterozygous 700C-T transition in the WDR45 gene, resulting in an arg234-to-ter (R234X) substitution.
In a 28-year-old woman with neurodegeneration with brain iron accumulation-5 (NBIA5; 300894), Saitsu et al. (2013) identified a heterozygous de novo 516G-C transversion in the last base of exon 8 of the WDR45 gene, resulting in a 22-bp frameshift insertion and premature termination (Asp174ValfsTer29). The mutation was identified by exome sequencing and was not found in several large control exome databases. Patient lymphoblastoid cells showed exclusive expression of the mutant transcript, suggesting X inactivation of the wildtype allele. There were decreased levels of mutant protein, suggesting that it is unstable and degraded. Patient cells showed impaired autophagic flux. Immunofluorescence studies showed the accumulation of autophagic structures in patient cells, consistent with improper autophagosome formation.
In a 40-year-old Japanese woman with neurodegeneration with brain iron accumulation-5 (NBIA5; 300894), originally reported by Kimura et al. (2013), Saitsu et al. (2013) identified a heterozygous de novo 1-bp duplication (437dupA) in the WDR45 gene, resulting in a frameshift and premature termination (Leu148AlafsTer3). The mutation was not found in several large control exome databases. There were decreased levels of mutant protein, suggesting that it is unstable and degraded. Patient cells showed impaired autophagic flux. Immunofluorescence studies showed the accumulation of autophagic structures in patient cells, consistent with improper autophagosome formation.
In a 51-year-old woman with neurodegeneration with brain iron accumulation-5 (NBIA5; 300894), Saitsu et al. (2013) identified a de novo heterozygous 637C-T transition in the WDR45 gene, resulting in a gln213-to-ter (Q213X) substitution. The mutation was not found in several large control exome databases. Patient lymphoblastoid cells showed exclusive expression of the mutant transcript, suggesting X inactivation of the wildtype allele. There were decreased levels of mutant protein, suggesting that it is unstable and degraded. Patient cells showed impaired autophagic flux. Immunofluorescence studies showed the accumulation of autophagic structures in patient cells, consistent with improper autophagosome formation.
Haack, T. B., Hogarth, P., Kruer, M. C., Gregory, A., Wieland, T., Schwarzmayr, T., Graf, E., Sanford, L., Meyer, E., Kara, E., Cuno, S. M., Harik, S. I., and 21 others. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am. J. Hum. Genet. 91: 1144-1149, 2012. [PubMed: 23176820] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.019]
Kimura, Y., Sato, N., Sugai, K., Maruyama, S., Ota, M., Kamiya, K., Ito, K., Nakata, Y., Sasaki, M., Sugimoto, H. MRI, MR spectroscopy, and diffusion tensor imaging findings in patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). Brain Dev. 35: 458-461, 2013. [PubMed: 22892189] [Full Text: https://doi.org/10.1016/j.braindev.2012.07.008]
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]
Saitsu, H., Nishimura, T., Muramatsu, K., Kodera, H., Kumada, S., Sugai, K., Kasai-Yoshida, E., Sawaura, N., Nishida, H., Hoshino, A., Ryujin, F., Yoshioka, S., and 9 others. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nature Genet. 45: 445-449, 2013. [PubMed: 23435086] [Full Text: https://doi.org/10.1038/ng.2562]