This report describes neurodegeneration with brain iron accumulation 5, which is a subtype of neurodegeneration with brain iron accumulation. The human gene implicated is WDR45, which encodes WD repeat domain 45. There is one moderate-scoring fly ortholog, Dmel\Wdr45, for which multiple genetic reagents, including classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
A UAS construct of the human gene Hsap\WDR45 has been introduced into flies. Functional complementation (heterologous rescue) of null mutations in Dmel\Wdr45 by expression of the human construct has been demonstrated.
Pan-neuronal RNAi knockdown of Dmel\Wdr45 results in progressive locomotor deficits. Flies bearing a null allele of Dmel\Wdr45 exhibit defects in axon guidance, branching, and connectivity during embryogenesis, and defects in the larval neuromuscular junction. Affected adults exhibit locomotor and seizure phenotypes, along with decreased fertility and lifespan, iron dyshomeostasis, and defects in autophagy. Pan-neuronal expression of wild-type Wdr45 or of Hsap\WDR45 rescues the locomotor and seizure phenotypes.
[updated Feb. 2026 by FlyBase; FBrf0222196]
Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia. Age at onset, severity, and cognitive involvement are variable (review by Gregory et al., 2009; pubmed:18981035). [from MIM:234200; 2016.03.29]
[NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5; NBIA5](https://omim.org/entry/300894)
[WD REPEAT-CONTAINING PROTEIN 45; WDR45](https://omim.org/entry/300526)
NBIA5, sometimes referred to as 'static encephalopathy of childhood with neurodegeneration in adulthood (SENDA),' is an X-linked neurodegenerative disorder characterized by global developmental delay in early childhood that is essentially static, with slow motor and cognitive gains until adolescence or early adulthood. In young adulthood, affected individuals develop progressive dystonia, parkinsonism, extrapyramidal signs, and dementia resulting in severe disability. Brain MRI shows iron accumulation in the globus pallidus and substantia nigra. A characteristic finding is T1-weighted hyperintensity surrounding a central band of hypointensity in the substantia nigra. Cerebral and cerebellar atrophy are also observed (summary by Haack et al., 2012, pubmed:23176820 and Saitsu et al., 2013, pubmed:23435086). [from MIM:300894; 2026.02.27]
Neurodegeneration with brain iron accumulation-5 (NBIA5) is caused by de novo heterozygous or hemizygous mutation in the WDR45 gene on chromosome Xp11. [from MIM:300894; 2026.02.27]
WDR45 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, pubmed:23435086). [from MIM:300526; 2026.02.27]
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, pubmed:15602573).
One to one (1 human to 1 Drosophila); WDR45 has one moderate-scoring Drosophila ortholog, Wdr45.
High-scoring ortholog of human WDR45B; moderate-scoring ortholog of human WDR45 (1 Drosophila to 2 human).
