WDR45

Summary

WDR45 (WD repeat domain 45, HGNC:28912) is a protein-coding gene on chromosome Xp11.23, encoding WD repeat domain phosphoinositide-interacting protein 4 (Q9Y484). Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene has a pseudogene at chromosome 4q31.3. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity and full-length nature of some variants have not been determined.

Source: NCBI Gene 11152 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 476 total — 97 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 48
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001029896

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28912
Approved symbol	WDR45
Name	WD repeat domain 45
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	JM5, WIPI4, NBIA5
Ensembl gene	ENSG00000196998
Ensembl biotype	protein_coding
OMIM	300526
Entrez	11152

Gene structure

Transcript identifiers

Ensembl transcripts: 101 — 84 protein_coding, 8 protein_coding_CDS_not_defined, 7 retained_intron, 2 nonsense_mediated_decay

ENST00000322995, ENST00000356463, ENST00000367375, ENST00000376357, ENST00000376368, ENST00000376372, ENST00000396681, ENST00000419567, ENST00000423215, ENST00000433252, ENST00000460501, ENST00000465382, ENST00000465431, ENST00000465806, ENST00000471338, ENST00000472654, ENST00000473974, ENST00000474053, ENST00000475880, ENST00000475977, ENST00000476728, ENST00000480412, ENST00000485908, ENST00000486337, ENST00000496803, ENST00000634390, ENST00000634465, ENST00000634522, ENST00000634559, ENST00000634671, ENST00000634711, ENST00000634736, ENST00000634838, ENST00000634849, ENST00000634852, ENST00000634908, ENST00000634939, ENST00000634944, ENST00000635003, ENST00000635329, ENST00000635344, ENST00000635666, ENST00000636049, ENST00000636645, ENST00000905844, ENST00000905845, ENST00000905846, ENST00000905847, ENST00000905848, ENST00000905849, ENST00000905850, ENST00000905851, ENST00000905852, ENST00000905853, ENST00000905854, ENST00000905855, ENST00000905856, ENST00000905857, ENST00000905858, ENST00000905859, ENST00000905860, ENST00000905861, ENST00000905862, ENST00000905863, ENST00000905864, ENST00000905865, ENST00000905866, ENST00000905867, ENST00000905868, ENST00000905869, ENST00000905870, ENST00000905871, ENST00000905872, ENST00000905873, ENST00000918928, ENST00000918929, ENST00000918930, ENST00000918931, ENST00000918932, ENST00000918933, ENST00000918934, ENST00000918935, ENST00000918936, ENST00000954171, ENST00000954172, ENST00000954173, ENST00000954174, ENST00000954175, ENST00000954176, ENST00000954177, ENST00000954178, ENST00000954179, ENST00000954180, ENST00000954181, ENST00000954182, ENST00000954183, ENST00000954184, ENST00000954185, ENST00000954186, ENST00000954187, ENST00000954188

RefSeq mRNA: 2 — MANE Select: NM_001029896 NM_001029896, NM_007075

CCDS: CCDS14318, CCDS35250

Canonical transcript exons

ENST00000376372 — 11 exons

Exon	Start	End
ENSE00000670306	49077643	49077747
ENSE00001470345	49076645	49076750
ENSE00001555893	49074442	49074912
ENSE00003463387	49075136	49075281
ENSE00003506025	49076430	49076524
ENSE00003853921	49075866	49075945
ENSE00003860775	49079751	49079887
ENSE00003884204	49075364	49075465
ENSE00003886458	49078041	49078112
ENSE00003886820	49075545	49075753
ENSE00003888175	49077837	49077911

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.2586 / max 397.4319, expressed in 1820 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199232	28.2544	1812
199231	5.1156	1653
209681	1.2857	517
209682	0.7399	440
199233	0.5477	266
199235	0.2571	120
199234	0.0582	17

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.00	gold quality
mucosa of stomach	UBERON:0001199	97.87	gold quality
granulocyte	CL:0000094	97.54	gold quality
right adrenal gland	UBERON:0001233	97.51	gold quality
right adrenal gland cortex	UBERON:0035827	97.46	gold quality
left adrenal gland cortex	UBERON:0035825	97.37	gold quality
left adrenal gland	UBERON:0001234	97.35	gold quality
endocervix	UBERON:0000458	97.27	gold quality
right lobe of thyroid gland	UBERON:0001119	97.26	gold quality
left lobe of thyroid gland	UBERON:0001120	97.23	gold quality
body of stomach	UBERON:0001161	97.20	gold quality
adenohypophysis	UBERON:0002196	97.18	gold quality
adrenal cortex	UBERON:0001235	97.04	gold quality
body of uterus	UBERON:0009853	97.04	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.97	gold quality
body of pancreas	UBERON:0001150	96.95	gold quality
metanephros cortex	UBERON:0010533	96.95	gold quality
right ovary	UBERON:0002118	96.93	gold quality
corpus epididymis	UBERON:0004359	96.87	gold quality
blood	UBERON:0000178	96.84	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.83	gold quality
right atrium auricular region	UBERON:0006631	96.82	gold quality
lower esophagus	UBERON:0013473	96.81	gold quality
minor salivary gland	UBERON:0001830	96.78	gold quality
left ovary	UBERON:0002119	96.78	gold quality
left uterine tube	UBERON:0001303	96.75	gold quality
gastrocnemius	UBERON:0001388	96.72	gold quality
left coronary artery	UBERON:0001626	96.72	gold quality
right lung	UBERON:0002167	96.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.68	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	1019.73
E-CURD-88	no	799.91
E-GEOD-75367	no	421.92
E-MTAB-6142	no	133.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting WDR45, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-5571-3P	97.80	66.07	640
HSA-MIR-4512	95.26	63.08	371

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 29)

• we have identified mutations in WDR45 as a cause of a distinctive X-linked dominant form of neurodegeneration with brain iron accumulation (NBIA) (PMID:23176820)
• De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. (PMID:23435086)
• Mutations in WDR45 are associated with brain iron accumulation and X-linked disorders of neurodegeneration. (PMID:23687123)
• Mutations in WDR45 were associated with neurodegeneration with brain iron accumulation and neuropsychiatric syndromes. (PMID:24368176)
• An observed mutation of WDR45 (c.C868T:p.Q290X) seems to cause beta-propeller protein-associated neurodegeneration. (PMID:25263061)
• C19orf12 mutations were confirmed in our heterogeneous NBIA cohort, while WDR45 mutations appear to be restricted to the subtype showing encephalopathy in childhood with neurodegeneration in adulthood. (PMID:25592411)
• WDR45 mutation is associated with beta-propeller protein-associated neurodegeneration. (PMID:26481852)
• Inherited WDR45 variants are possible, albeit rare. Hemizygous germline variants in males can be viable, but likely result in a more severe NBIA phenotype. (PMID:26577041)
• Our findings indicate that hemizygous WDR45 mutations in males lead to severe epileptic encephalopathy. (PMID:27030146)
• It is an autophagy gene and its mutation causes SENDA/BPAN(beta-propeller protein associated neurodegeneration). (review) (PMID:27349079)
• Genetic analysis for WDR45 revealed that she had a splice site mutation (PMID:27349085)
• This study showed the WDR45 mutation complicated by infantile spasms. (PMID:28551038)
• WIPI3 and WIPI4 beta-propellers have roles as scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy (PMID:28561066)
• A rare male patient is reported with mutation in WDR45 and early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase. (PMID:28711740)
• This study showed that Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45. (PMID:29171013)
• This study showed that WDR45 genes account for disease of patients diagnosed with an Neurodegeneration with brain iron accumulation disorder. (PMID:29325618)
• Novel missense mutations in WDR45 were identified in female pediatric patients with developmental delay and/or epilepsy. Arg134Pro and p. Gly168Glu mutations showed accumulation of LC3-containing autophagic structures and enlarged cell volume in HeLa cells. (PMID:29981852)
• Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function (PMID:30169597)
• Beta-propeller protein-associated neurodegeneration (BPAN, OMIM 300894) is an X-linked neurodegenerative disorder caused by mutations in WDR45. Novel mutation in WDR45 impaired autophagy in cells thus this mutation is the cause for BPAN in this patient. (PMID:31332960)
• Phenotypic and Imaging Spectrum Associated With WDR45. (PMID:32387008)
• De novo variants in WDR45 underlie beta-propeller protein-associated neurodegeneration in five independent families. (PMID:33037762)
• Beta-propeller protein-associated neurodegeneration presenting Rett-like features: A case report and literature review. (PMID:33251766)
• Autophagic defects observed in fibroblasts from a patient with beta-propeller protein-associated neurodegeneration. (PMID:34325486)
• Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts. (PMID:34769084)
• Quantitative retrospective natural history modeling of WDR45-related developmental and epileptic encephalopathy - a systematic cross-sectional analysis of 160 published cases. (PMID:34818117)
• A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation. (PMID:34837396)
• WDR45 mutation dysregulates iron homeostasis by promoting the chaperone-mediated autophagic degradation of ferritin heavy chain in an ER stress/p38 dependent mechanism. (PMID:36940732)
• Variants in the WDR45 Gene Within the OPA-2 Locus Associate With Isolated X-Linked Optic Atrophy. (PMID:37819743)
• WDR45-dependent impairment of cell cycle in fibroblasts of patients with beta propeller protein-associated neurodegeneration (BPAN). (PMID:39265886)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdr45	ENSDARG00000090219
mus_musculus	Wdr45	ENSMUSG00000039382
rattus_norvegicus	Wdr45	ENSRNOG00000009749
caenorhabditis_elegans		WBGENE00012641

Paralogs (3): WIPI1 (ENSG00000070540), WDR45B (ENSG00000141580), WIPI2 (ENSG00000157954)

Protein

Protein identifiers

WD repeat domain phosphoinositide-interacting protein 4 — Q9Y484 (reviewed: Q9Y484)

Alternative names: WD repeat-containing protein 45

All UniProt accessions (25): A0A0U1RQG6, A0A0U1RQJ7, A0A0U1RQM7, A0A0U1RQR1, A0A0U1RQS7, A0A0U1RR06, A0A0U1RR42, A0A0U1RRJ2, A0A0U1RRJ9, A0A1B0GV56, Q9Y484, A0A1Y8EKY4, C9J0A8, C9J471, C9J5L0, C9J7Q8, C9JBX7, C9JE01, C9JUS5, C9JVT3, C9JYH8, G8JLI5, H0Y329, H7C4N7, H7C5B4

UniProt curated annotations — full annotation on UniProt →

Function. Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation. Binds phosphatidylinositol 3-phosphate (PtdIns3P). Activated by the STK11/AMPK signaling pathway upon starvation, WDR45 is involved in autophagosome assembly downstream of WIPI2, regulating the size of forming autophagosomes. Together with WIPI1, promotes ATG2 (ATG2A or ATG2B)-mediated lipid transfer by enhancing ATG2-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes. Probably recruited to membranes through its PtdIns3P activity.

Subunit / interactions. Interacts with WIPI1. Interacts with WIPI2. Interacts with ATG2A and ATG2B. Interacts with ULK1. May interact with the PRKAA1, PRKAA2, PRKAB1 and PRKAG1 subunits of the AMPK kinase. May interact with NUDC.

Subcellular location. Preautophagosomal structure. Cytoplasm.

Tissue specificity. Ubiquitously expressed, with high expression in skeletal muscle and heart. Weakly expressed in liver and placenta. Expression is down-regulated in pancreatic and in kidney tumors.

Disease relevance. Neurodegeneration with brain iron accumulation 5 (NBIA5) [MIM:300894] A neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. NBIA5 is 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. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated upon amino-acid starvation.

Domain organisation. The L/FRRG motif is required for recruitment to PtdIns3P.

Similarity. Belongs to the WD repeat PROPPIN family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y484-1	1	yes
Q9Y484-2	2
Q9Y484-3	3

RefSeq proteins (2): NP_001025067, NP_009006 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR048720	PROPPIN	Family

Pfam: PF21032

UniProt features (64 total): strand 28, mutagenesis site 10, repeat 7, helix 7, turn 4, splice variant 2, sequence variant 2, sequence conflict 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8KBX	ELECTRON MICROSCOPY	3.23
8KC3	ELECTRON MICROSCOPY	7
8Y1L	ELECTRON MICROSCOPY	7.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y484-F1	90.66	0.82

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (10):

Position	Phenotype
15	decreased interaction with atg2a. loss of interaction with atg2a; when associated with a-17.
16	no effect on interaction with atg2a.
17	decreased interaction with atg2a. loss of interaction with atg2a; when associated with a-15.
55	no effect on interaction with atg2a.
109	no effect on interaction with atg2a.
111	no effect on interaction with atg2a.
112	no effect on interaction with atg2a.
113	loss of interaction with ampk. no effect on interaction with atg2a.
114	no effect on interaction with atg2a.
232–233	no effect on interaction with atg2a.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy

MSigDB gene sets: 270 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_VACUOLE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_VACUOLE_ORGANIZATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_MACROAUTOPHAGY, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_POLYSACCHARIDE_CATABOLIC_PROCESS, MARTINEZ_RB1_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (9): autophagosome assembly (GO:0000045), autophagy of mitochondrion (GO:0000422), pexophagy (GO:0000425), autophagy (GO:0006914), cellular response to starvation (GO:0009267), protein localization to phagophore assembly site (GO:0034497), nucleophagy (GO:0044804), glycophagy (GO:0061723), positive regulation of autophagosome assembly (GO:2000786)

GO Molecular Function (7): protein kinase binding (GO:0019901), protein-macromolecule adaptor activity (GO:0030674), phosphatidylinositol-3-phosphate binding (GO:0032266), phosphatidylinositol-3,5-bisphosphate binding (GO:0080025), phosphatidylinositol phosphate binding (GO:1901981), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (4): phagophore assembly site (GO:0000407), cytosol (GO:0005829), phagophore assembly site membrane (GO:0034045), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Autophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
macroautophagy	3
cellular anatomical structure	3
autophagosome assembly	2
phosphatidylinositol phosphate binding	2
binding	2
cytoplasm	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
autophagy	1
autophagy of peroxisome	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
intracellular protein localization	1
glycogen catabolic process	1
positive regulation of macroautophagy	1
positive regulation of vacuole organization	1
positive regulation of organelle assembly	1
regulation of autophagosome assembly	1
kinase binding	1
protein binding	1
molecular adaptor activity	1
phosphatidylinositol bisphosphate binding	1
phospholipid binding	1
phagophore assembly site	1
membrane	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1130 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WDR45	ATG2A	Q2TAZ0	993
WDR45	ATG2B	Q96BY7	984
WDR45	OTUD7B	Q6GQQ9	849
WDR45	EPG5	Q9HCE0	807
WDR45	ATG5	Q9H1Y0	779
WDR45	ATG12	O94817	778
WDR45	C19orf12	Q9NSK7	738
WDR45	GABARAP	O95166	721
WDR45	DCAF17	Q5H9S7	715
WDR45	PANK2	Q9BZ23	712
WDR45	COASY	Q13057	708
WDR45	RB1CC1	Q8TDY2	641
WDR45	WIPI1	Q5MNZ9	637
WDR45	TECPR2	O15040	625
WDR45	PLA2G6	O60733	623

IntAct

34 interactions, top by confidence:

A	B	Type	Score
ATG2B	WDR45	psi-mi:“MI:0915”(physical association)	0.730
HDAC11	CLUH	psi-mi:“MI:0914”(association)	0.640
ATG2A	WDR45	psi-mi:“MI:0915”(physical association)	0.620
WDR45	ATG2A	psi-mi:“MI:0914”(association)	0.620
ATG2A	TOMM40	psi-mi:“MI:0914”(association)	0.610
SLC25A11	POTEI	psi-mi:“MI:0914”(association)	0.530
ATG2B	TKT	psi-mi:“MI:0914”(association)	0.530
Atg2a	BAG2	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
HTT		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
ATG2A	TTC4	psi-mi:“MI:0914”(association)	0.350
ATG2A	DNAJB1	psi-mi:“MI:0914”(association)	0.350
ATG2A	SUPT5H	psi-mi:“MI:0914”(association)	0.350
ATG13	ENAH	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CFAP184	TARS3	psi-mi:“MI:0914”(association)	0.350
DNAJA2	DENND11	psi-mi:“MI:0914”(association)	0.350
ARSK	CLGN	psi-mi:“MI:0914”(association)	0.350
SPAST	CBLIF	psi-mi:“MI:0914”(association)	0.350
LHX6	KDM5C	psi-mi:“MI:0914”(association)	0.350
LCN8	LRRC41	psi-mi:“MI:0914”(association)	0.350
MOSPD3	TSN	psi-mi:“MI:0914”(association)	0.350
PLGRKT	VPS13C	psi-mi:“MI:0914”(association)	0.350
CISD1	CISD2	psi-mi:“MI:0914”(association)	0.350
DNAJA2	ENC1	psi-mi:“MI:0914”(association)	0.350
	ILVBL	psi-mi:“MI:0914”(association)	0.350
POC1A	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
CEP89	CCDC66	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (69): WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Proximity Label-MS), WDR45 (Proximity Label-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS), WDR45 (Affinity Capture-MS)

ESM2 similar proteins: A1CBB8, A1CTE6, A1DE24, A2QCU8, A2RAG5, A6QTX7, A6SJ85, A7EW77, A7KAM8, B6Q4Z5, B8M7Q5, B8N4F5, I1RKA1, P0CS28, P0CS29, Q00659, Q0CKB1, Q0CW30, Q0CY32, Q0U2J8, Q1DKJ3, Q2GSJ9, Q2GV40, Q2U6D5, Q2UFN8, Q2UM42, Q2URJ0, Q4IBR4, Q4IQC1, Q4P4N1, Q4WKB2, Q4WVD0, Q524W4, Q5B464, Q5BH53, Q5MNZ9, Q5QA94, Q5U2Y0, Q6C044, Q6DCN1

Diamond homologs: A1CBB8, A1DE24, A2RAG5, A3GFE3, A5DHI9, A5DVU7, A6QTX7, A6SJ85, A7A258, A7EW77, A7KAM8, A7TPY4, I1RKA1, O16466, P0CS28, P0CS29, P43601, P50079, Q0CW30, Q0U2J8, Q0WPK3, Q1DKJ3, Q2GV40, Q2U6D5, Q4P4N1, Q4WVD0, Q524W4, Q54NA2, Q59P11, Q5ABA6, Q5BH53, Q5MNZ6, Q5MNZ9, Q5QA94, Q5QJC0, Q5R7W0, Q5ZHN3, Q5ZL16, Q640T2, Q68F45

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PIP3	“up-regulates activity”	WDR45	“chemical activation”
AMPK	“up-regulates activity”	WDR45	phosphorylation
NUAK2	“up-regulates activity”	WDR45	phosphorylation
BRSK2	“up-regulates activity”	WDR45	phosphorylation
WDR45	“up-regulates activity”	ATG2A	binding
WDR45	“up-regulates activity”	ATG2B	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

476 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	97
Likely pathogenic	44
Uncertain significance	120
Likely benign	122
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070071	NM_001029896.2(WDR45):c.332_338del (p.Arg111fs)	Pathogenic
1072452	NM_001029896.2(WDR45):c.797_798del (p.Leu266fs)	Pathogenic
1076011	NM_001029896.2(WDR45):c.938del (p.Gly313fs)	Pathogenic
1184945	NM_001029896.2(WDR45):c.908del (p.Pro303fs)	Pathogenic
1191932	NM_001029896.2(WDR45):c.436+2T>C	Pathogenic
1195397	NM_001029896.2(WDR45):c.340_341+2del	Pathogenic
1320133	NM_001029896.2(WDR45):c.604del (p.Gln202fs)	Pathogenic
1329495	NM_001029896.2(WDR45):c.891_892insT (p.Ala298fs)	Pathogenic
1329904	NM_001029896.2(WDR45):c.828-3C>A	Pathogenic
1335977	NM_001029896.2(WDR45):c.501del (p.Ser168fs)	Pathogenic
1386002	NM_001029896.2(WDR45):c.1037_1038del (p.Glu346fs)	Pathogenic
1392173	NM_001029896.2(WDR45):c.880del (p.Gln294fs)	Pathogenic
1486731	NM_001029896.2(WDR45):c.236-21A>G	Pathogenic
1709095	NM_001029896.2(WDR45):c.787_790dup (p.Phe264fs)	Pathogenic
1709883	NM_001029896.2(WDR45):c.488del (p.Gly163fs)	Pathogenic
1803675	NM_001029896.2(WDR45):c.726-1G>A	Pathogenic
1810120	NM_001029896.2(WDR45):c.436+2T>G	Pathogenic
1810241	NM_001029896.2(WDR45):c.616del (p.Thr205_Val206insTer)	Pathogenic
2044157	NM_001029896.2(WDR45):c.922_928del (p.Cys308fs)	Pathogenic
2083404	NM_001029896.2(WDR45):c.1010_1011del (p.Phe337fs)	Pathogenic
2125781	NM_001029896.2(WDR45):c.865_874del (p.Gln289fs)	Pathogenic
212593	NM_001029896.2(WDR45):c.516+1G>T	Pathogenic
212594	NM_001029896.2(WDR45):c.827+2_827+3del	Pathogenic
2132683	NM_001029896.2(WDR45):c.827+5G>T	Pathogenic
2138573	NM_001029896.2(WDR45):c.879_880del (p.Gln294fs)	Pathogenic
242347	NM_001029896.2(WDR45):c.611G>A (p.Gly204Asp)	Pathogenic
2425684	NC_000023.10:g.(?48932462)(48935755_?)del	Pathogenic
2500674	NM_001029896.2(WDR45):c.516+2T>C	Pathogenic
2626856	NM_001029896.2(WDR45):c.618dup (p.Val207fs)	Pathogenic
2630550	NM_001029896.2(WDR45):c.951del (p.Lys318fs)	Pathogenic

SpliceAI

2685 predictions. Top by Δscore:

Variant	Effect	Δscore
X:49075356:GTACT:G	donor_loss	1.0000
X:49075358:ACT:A	donor_loss	1.0000
X:49075359:CTC:C	donor_loss	1.0000
X:49075360:TCA:T	donor_loss	1.0000
X:49075361:CAC:C	donor_loss	1.0000
X:49075362:A:AC	donor_gain	1.0000
X:49075363:C:CA	donor_gain	1.0000
X:49075363:CG:C	donor_gain	1.0000
X:49075431:C:CT	acceptor_gain	1.0000
X:49075466:C:CC	acceptor_gain	1.0000
X:49076428:A:AC	donor_gain	1.0000
X:49076428:AC:A	donor_gain	1.0000
X:49076429:C:CA	donor_gain	1.0000
X:49076429:C:CC	donor_gain	1.0000
X:49076457:CAA:C	donor_gain	1.0000
X:49076458:AAA:A	donor_gain	1.0000
X:49076520:CGATC:C	acceptor_gain	1.0000
X:49076521:GATC:G	acceptor_gain	1.0000
X:49076522:ATC:A	acceptor_gain	1.0000
X:49076523:TC:T	acceptor_gain	1.0000
X:49076523:TCCTG:T	acceptor_loss	1.0000
X:49076524:CC:C	acceptor_gain	1.0000
X:49076525:C:CC	acceptor_gain	1.0000
X:49076525:C:CG	acceptor_loss	1.0000
X:49076526:T:G	acceptor_loss	1.0000
X:49076531:G:C	acceptor_gain	1.0000
X:49076531:G:GC	acceptor_gain	1.0000
X:49076535:C:CT	acceptor_gain	1.0000
X:49076537:C:CT	acceptor_gain	1.0000
X:49076643:A:AC	donor_gain	1.0000

AlphaMissense

2380 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:49074842:G:C	F348L	1.000
X:49074842:G:T	F348L	1.000
X:49074844:A:G	F348L	1.000
X:49074864:C:T	G341E	1.000
X:49074876:A:G	F337S	1.000
X:49074897:C:A	G330V	1.000
X:49074897:C:T	G330E	1.000
X:49074898:C:A	G330W	1.000
X:49074905:G:C	C327W	1.000
X:49074906:C:T	C327Y	1.000
X:49075141:A:T	V323D	1.000
X:49075179:G:C	C310W	1.000
X:49075180:C:T	C310Y	1.000
X:49075181:A:G	C310R	1.000
X:49075224:C:A	W295C	1.000
X:49075224:C:G	W295C	1.000
X:49075375:G:C	N272K	1.000
X:49075375:G:T	N272K	1.000
X:49075399:A:C	F264L	1.000
X:49075399:A:T	F264L	1.000
X:49075400:A:C	F264C	1.000
X:49075400:A:G	F264S	1.000
X:49075401:A:C	F264V	1.000
X:49075401:A:G	F264L	1.000
X:49075401:A:T	F264I	1.000
X:49075405:A:C	H262Q	1.000
X:49075405:A:T	H262Q	1.000
X:49075407:G:C	H262D	1.000
X:49075409:A:T	V261D	1.000
X:49075412:G:A	T260I	1.000

dbSNP variants (sampled 300 via entrez): RS1000142676 (X:49087625 G>C), RS1000326775 (X:49097000 T>A), RS1000987363 (X:49078483 T>C), RS1001094042 (X:49089219 C>T), RS1001392872 (X:49100136 A>G), RS1001593256 (X:49080654 G>A,T), RS1001940761 (X:49080195 G>A), RS1002046049 (X:49091048 C>T), RS1002098155 (X:49091308 G>A), RS1002152437 (X:49092336 T>G), RS1002343140 (X:49101387 G>C,T), RS1002998010 (X:49084475 G>A), RS1003096519 (X:49094327 T>C), RS1003646033 (X:49074842 G>A), RS1003698454 (X:49075334 G>A)

Disease associations

OMIM: gene MIM:300526 | disease phenotypes: MIM:300894, MIM:311050, MIM:300864, MIM:141500, MIM:234200, MIM:615179

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration with brain iron accumulation 5	Definitive	X-linked
X-linked complex neurodevelopmental disorder	Definitive	X-linked
infantile spasms	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (9): neurodegeneration with brain iron accumulation 5 (MONDO:0010476), optic atrophy 2 (MONDO:0010698), X-linked cerebral-cerebellar-coloboma syndrome syndrome (MONDO:0010464), migraine, familial hemiplegic, 1 (MONDO:0020756), neurodegeneration with brain iron accumulation (MONDO:0018307), oculocutaneous albinism type 7 (MONDO:0014070), intellectual disability (MONDO:0001071), X-linked complex neurodevelopmental disorder (MONDO:0100148), infantile spasms (MONDO:0018097)

Orphanet (7): Beta-propeller protein-associated neurodegeneration (Orphanet:329284), Early-onset X-linked optic atrophy (Orphanet:98890), X-linked cerebral-cerebellar-coloboma syndrome (Orphanet:163961), Familial or sporadic hemiplegic migraine (Orphanet:569), Neurodegeneration with brain iron accumulation (Orphanet:385), Oculocutaneous albinism type 7 (Orphanet:352745), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000496	Abnormality of eye movement
HP:0000565	Esotropia
HP:0000577	Exotropia
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000707	Abnormality of the nervous system
HP:0000718	Aggressive behavior
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0000743	Frontal release signs
HP:0000750	Delayed speech and language development
HP:0001022	Albinism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001423	X-linked dominant inheritance
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002180	Neurodegeneration
HP:0002304	Akinesia

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C536890	Hemiplegic migraine, familial type 1 (supp.)
C538421	Neurodegeneration with brain iron accumulation (NBIA) (supp.)
C537125	Optic atrophy, X-linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression, increases expression	3
Cyclosporine	increases expression	3
bisphenol A	affects expression, increases expression	2
Tunicamycin	increases expression	2
afuresertib	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
CD 437	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Azathioprine	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Selenium	increases expression	1
Smoke	decreases expression	1
Urethane	increases expression	1

Cellosaurus cell lines

17 cell lines: 7 finite cell line, 5 transformed cell line, 3 cancer cell line, 2 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2SP	GM27869	Transformed cell line	Female
CVCL_A9ZH	GM27930	Induced pluripotent stem cell	Female
CVCL_B2LD	Abcam HeLa WDR45 KO	Cancer cell line	Female
CVCL_B5L6	HAP1 WDR45 (-) 2	Cancer cell line	Male
CVCL_C0LH	GM28284	Finite cell line	Female
CVCL_C0LI	GM28285	Transformed cell line	Female
CVCL_C0LJ	GM28286	Finite cell line	Female
CVCL_C0LM	GM28332	Finite cell line	Female
CVCL_C0LN	GM28333	Transformed cell line	Female
CVCL_C6PZ	FDHPIi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

232 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01413711	PHASE4	WITHDRAWN	An Open-Label, Single and Multiple Oral Dose Pharmacokinetic Study of Vigabatrin in Infants With Infantile Spasms
NCT02092883	PHASE4	COMPLETED	Evaluation of Neuroinflammation in Children With Infantile Spasms
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01575639	PHASE3	COMPLETED	Prednisolone in Infantile Spasms- High Dose Versus Usual Dose
NCT01828437	PHASE3	COMPLETED	Addition of Pyridoxine to Prednisolone in Infantile Spasms
NCT02299115	PHASE3	WITHDRAWN	Prednisolone Versus Vigabatrin in the First-line Treatment of Infantile Spasms
NCT02953548	PHASE3	COMPLETED	Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms (GWPCARE7)
NCT02954887	PHASE3	COMPLETED	Phase 3 Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms: Open-label Extension Phase (GWPCARE7)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00441896	PHASE2	COMPLETED	A Randomized, Controlled Trial of Ganaxolone in Patients With Infantile Spasms
NCT00442104	PHASE2	TERMINATED	Open-label Extension to Protocol 1042-0500
NCT02829827	PHASE2	TERMINATED	A Phase 2 Study of Radiprodil in Subjects With Drug-resistant Infantile Spasms (IS)
NCT03976076	PHASE2	TERMINATED	A Study of Orally Administered JBPOS0101 in Refractory Infantile Spasms Patients
NCT06819670	PHASE2	RECRUITING	A Study to Prevent Infantile Spasms Relapse
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03572114	Not specified	UNKNOWN	Imaging Neuromelanin and Iron in Dystonia/Parkinsonism
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT01006811	PHASE2/PHASE3	COMPLETED	Use of the Modified Atkins Diet in Infantile Spasms
NCT01549288	PHASE2/PHASE3	WITHDRAWN	Trial of the Modified Atkins Diet in Infantile Spasms Refractory to Hormonal Therapy
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT06201897	PHASE2/PHASE3	RECRUITING	Cortical Excitability in West Syndrome Using Transcranial Magnetic Stimulation
NCT00001325	Not specified	COMPLETED	Metabolic Abnormalities in Children With Epilepsy
NCT00552045	Not specified	COMPLETED	Epilepsy Phenome/Genome Project
NCT00968136	Not specified	COMPLETED	Short-term Ketogenic Diet as Compared With Conventional Long-term Trial in Refractory Infantile Spasms: A Randomized, Controlled Study
NCT01073579	Not specified	COMPLETED	Sabril Patient Registry
NCT01367964	Not specified	UNKNOWN	Prevention of West Syndrome With Low-dose Adrenocorticotropin Hormone (ACTH)