DEF8

Summary

DEF8 (differentially expressed in FDCP 8 homolog, HGNC:25969) is a protein-coding gene on chromosome 16q24.3, encoding Differentially expressed in FDCP 8 homolog (Q6ZN54). Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts.

Predicted to enable zinc ion binding activity. Predicted to be involved in lysosome localization; positive regulation of bone resorption; and positive regulation of ruffle assembly.

Source: NCBI Gene 54849 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 114 total
• MANE Select transcript: NM_001242818

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25969
Approved symbol	DEF8
Name	differentially expressed in FDCP 8 homolog
Location	16q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20186
Ensembl gene	ENSG00000140995
Ensembl biotype	protein_coding
Entrez	54849

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 40 protein_coding, 6 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000268676, ENST00000418391, ENST00000561741, ENST00000561784, ENST00000561959, ENST00000562044, ENST00000562163, ENST00000562578, ENST00000562986, ENST00000563594, ENST00000563795, ENST00000563805, ENST00000563848, ENST00000564379, ENST00000564836, ENST00000566079, ENST00000566820, ENST00000567243, ENST00000567874, ENST00000567884, ENST00000567999, ENST00000568096, ENST00000568760, ENST00000569061, ENST00000569453, ENST00000569803, ENST00000570182, ENST00000610455, ENST00000617948, ENST00000875119, ENST00000875120, ENST00000875121, ENST00000875122, ENST00000875123, ENST00000875124, ENST00000875125, ENST00000875126, ENST00000875127, ENST00000875128, ENST00000875129, ENST00000875130, ENST00000875131, ENST00000875132, ENST00000875133, ENST00000921167, ENST00000921168, ENST00000921169, ENST00000968043, ENST00000968044, ENST00000968045

RefSeq mRNA: 9 — MANE Select: NM_001242818 NM_001242816, NM_001242817, NM_001242818, NM_001242819, NM_001242820, NM_001242821, NM_001242822, NM_017702, NM_207514

CCDS: CCDS10989, CCDS45555, CCDS58493, CCDS58494, CCDS58495, CCDS58496

Canonical transcript exons

ENST00000563594 — 13 exons

Exon	Start	End
ENSE00001174624	89962012	89962125
ENSE00001267425	89964170	89964310
ENSE00001267510	89965861	89968060
ENSE00001707353	89949417	89949513
ENSE00003476382	89959014	89959155
ENSE00003531179	89954243	89954376
ENSE00003534099	89964466	89964575
ENSE00003545172	89960931	89961095
ENSE00003572591	89961737	89961864
ENSE00003590349	89948755	89948814
ENSE00003601332	89957511	89957660
ENSE00003659770	89963363	89963443
ENSE00003685455	89955169	89955266

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 98.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.0027 / max 123.7697, expressed in 1807 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155682	18.9851	1805
155683	0.9358	193
155684	0.0818	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.12	gold quality
cerebellar hemisphere	UBERON:0002245	98.02	gold quality
cerebellar cortex	UBERON:0002129	97.96	gold quality
cerebellum	UBERON:0002037	97.21	gold quality
granulocyte	CL:0000094	96.87	gold quality
right frontal lobe	UBERON:0002810	96.72	gold quality
anterior cingulate cortex	UBERON:0009835	96.19	gold quality
cingulate cortex	UBERON:0003027	96.11	gold quality
monocyte	CL:0000576	96.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.91	gold quality
mononuclear cell	CL:0000842	95.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.85	gold quality
blood	UBERON:0000178	95.80	gold quality
mucosa of stomach	UBERON:0001199	95.73	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.73	gold quality
leukocyte	CL:0000738	95.69	gold quality
prefrontal cortex	UBERON:0000451	95.67	gold quality
cerebellar vermis	UBERON:0004720	95.64	gold quality
substantia nigra pars compacta	UBERON:0001965	95.45	gold quality
lower esophagus mucosa	UBERON:0035834	95.32	gold quality
spinal cord	UBERON:0002240	95.30	gold quality
left uterine tube	UBERON:0001303	95.22	gold quality
lower esophagus	UBERON:0013473	95.21	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.21	gold quality
metanephros cortex	UBERON:0010533	95.16	gold quality
amygdala	UBERON:0001876	94.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.98	gold quality
nucleus accumbens	UBERON:0001882	94.97	gold quality
right ovary	UBERON:0002118	94.85	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting DEF8, 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-4425	100.00	67.59	1049
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4472	99.56	66.08	1478

Literature-anchored findings (GeneRIF, showing 2)

• DEF8 and Autophagy-Associated Genes Are Altered in Mild Cognitive Impairment, Probable Alzheimer’s Disease Patients, and a Transgenic Model of the Disease. (PMID:33612542)
• Involvement of autophagic protein DEF8 in Lewy bodies. (PMID:35921708)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	def8	ENSDARG00000068208
mus_musculus	Def8	ENSMUSG00000001482
rattus_norvegicus	Def8	ENSRNOG00000000264
drosophila_melanogaster	DEF8	FBGN0046296
caenorhabditis_elegans		WBGENE00013235

Paralogs (4): RUBCNL (ENSG00000102445), RUBCN (ENSG00000145016), PLEKHM3 (ENSG00000178385), PLEKHM1 (ENSG00000225190)

Protein

Protein identifiers

Differentially expressed in FDCP 8 homolog — Q6ZN54 (reviewed: Q6ZN54)

All UniProt accessions (12): Q6ZN54, H3BMP4, H3BMT5, H3BNN0, H3BQ81, H3BQH5, H3BQX9, H3BRA7, H3BSH6, H3BT01, H3BT87, H3BTS7

UniProt curated annotations — full annotation on UniProt →

Function. Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts. Involved in bone resorption.

Subunit / interactions. Interacts (via C-terminus) with PLEKHM1; this interaction is weak but increased in a RAB7A-dependent manner.

Similarity. Belongs to the DEF8 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q6ZN54-1	1	yes
Q6ZN54-2	2
Q6ZN54-3	3
Q6ZN54-4	4
Q6ZN54-5	5
Q6ZN54-6	6

RefSeq proteins (9): NP_001229745, NP_001229746, NP_001229747, NP_001229748, NP_001229749, NP_001229750, NP_001229751, NP_060172, NP_997397 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002219	PKC_DAG/PE	Domain
IPR025258	RH_dom	Domain
IPR046349	C1-like_sf	Homologous_superfamily
IPR047983	DEF8_C1	Domain
IPR051366	DEF8	Family

Pfam: PF00130, PF13901

UniProt features (19 total): splice variant 6, modified residue 5, zinc finger region 2, sequence conflict 2, chain 1, sequence variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZN54-F1	76.04	0.54

Functional residue map

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

Post-translational modifications (5): 1, 1, 1, 1, 501

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 149 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_REGULATION_OF_RUFFLE_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, WEI_MYCN_TARGETS_WITH_E_BOX, NIKOLSKY_BREAST_CANCER_16Q24_AMPLICON, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, ZIC1_01, GOBP_REGULATION_OF_BONE_REMODELING, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, TIEN_INTESTINE_PROBIOTICS_24HR_UP, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (3): lysosome localization (GO:0032418), positive regulation of bone resorption (GO:0045780), positive regulation of ruffle assembly (GO:1900029)

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vacuolar localization	1
regulation of bone resorption	1
bone resorption	1
positive regulation of multicellular organismal process	1
ruffle assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
regulation of ruffle assembly	1
transition metal ion binding	1
binding	1
cation binding	1

Protein interactions and networks

STRING

626 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DEF8	DBNDD1	Q9H9R9	668
DEF8	SPATA33	Q96N06	599
DEF8	SPIRE2	Q8WWL2	590
DEF8	TCF25	Q9BQ70	577
DEF8	CDK10	Q15131	567
DEF8	ZNF276	Q8N554	559
DEF8	RALY	Q9UKM9	554
DEF8	MC1R	Q01726	548
DEF8	NDEL1	Q9GZM8	548
DEF8	PRSS36	Q5K4E3	534
DEF8	MTHFSD	Q2M296	505
DEF8	SLC45A2	Q9UMX9	480
DEF8	DRC4	O95995	464
DEF8	BNC2	Q6ZN30	447
DEF8	SPATA2L	Q8IUW3	447

IntAct

10 interactions, top by confidence:

A	B	Type	Score
DEF8	CFTR	psi-mi:“MI:0915”(physical association)	0.370
DEF8	DPYSL4	psi-mi:“MI:0914”(association)	0.350
PLEKHM3	ENDOD1	psi-mi:“MI:0914”(association)	0.350
DEF8	APAF1	psi-mi:“MI:0914”(association)	0.350
DEF8	SERPINA1	psi-mi:“MI:0914”(association)	0.350
SLC4A5	ESYT2	psi-mi:“MI:0914”(association)	0.350
FMR1	DEF8	psi-mi:“MI:0915”(physical association)	0.000
DEF8		psi-mi:“MI:0915”(physical association)	0.000
RSPH1	DEF8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (88): WDFY3 (Affinity Capture-MS), PKN3 (Affinity Capture-MS), APAF1 (Affinity Capture-MS), PLCB1 (Affinity Capture-MS), RADIL (Affinity Capture-MS), HPS5 (Affinity Capture-MS), KDM5C (Affinity Capture-MS), MSTO1 (Affinity Capture-MS), ZMYM6 (Affinity Capture-MS), STIL (Affinity Capture-MS), MCM8 (Affinity Capture-MS), C5orf22 (Affinity Capture-MS), TUBE1 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), NRD1 (Affinity Capture-MS)

ESM2 similar proteins: A1L3C1, A2AWP8, A2RRU4, A6QM06, A6QNS9, E1BBQ2, F1LQY6, G3V9M2, O43189, O94827, P29372, P29590, P41155, P97260, Q01113, Q02833, Q04841, Q0P5I0, Q12770, Q13387, Q13505, Q29RM4, Q32L49, Q3V1H9, Q5MNU5, Q5R5M3, Q66T02, Q69Z89, Q6GQT6, Q6IPT2, Q6RFZ7, Q6ZN54, Q70EL4, Q7Z6G3, Q8BQB4, Q8C4U2, Q8N1F8, Q8N554, Q8WWW0, Q8WXF8

Diamond homologs: A5PJM7, A7E316, O01738, Q08AW4, Q22744, Q3TD16, Q4V8I4, Q5PQS0, Q6DDJ3, Q6DJB3, Q6ZN54, Q6ZWE6, Q7T0P6, Q7TSI1, Q80U62, Q8BM47, Q92622, Q99J78, Q9H714, Q9VTT9, Q9Y4G2, Q08DX0, Q8BIJ7, Q8IWE5, Q8TEQ0, Q96T51, Q9D3S3, P34125, P09215, P28867, Q05655, Q5PU49, Q9Z1S3, Q5R4V2, Q5R5R4, Q7L099, Q8WXA3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3137 predictions. Top by Δscore:

Variant	Effect	Δscore
16:89954237:CCTCA:C	acceptor_loss	1.0000
16:89954238:CTCAG:C	acceptor_loss	1.0000
16:89954240:CAG:C	acceptor_loss	1.0000
16:89954241:AGGT:A	acceptor_gain	1.0000
16:89954242:GGT:G	acceptor_gain	1.0000
16:89954242:GGTG:G	acceptor_gain	1.0000
16:89955167:A:AG	acceptor_gain	1.0000
16:89955167:A:G	acceptor_loss	1.0000
16:89955168:G:GG	acceptor_gain	1.0000
16:89955168:GA:G	acceptor_gain	1.0000
16:89955264:GTG:G	donor_gain	1.0000
16:89955267:GT:G	donor_loss	1.0000
16:89955268:T:A	donor_loss	1.0000
16:89957239:G:GT	donor_gain	1.0000
16:89957239:G:T	donor_gain	1.0000
16:89957509:AG:A	acceptor_gain	1.0000
16:89957510:GG:G	acceptor_gain	1.0000
16:89957658:AAGG:A	donor_loss	1.0000
16:89957659:AGGT:A	donor_loss	1.0000
16:89957661:G:GA	donor_loss	1.0000
16:89959009:TGCAG:T	acceptor_loss	1.0000
16:89959010:GCAGG:G	acceptor_loss	1.0000
16:89959011:CAG:C	acceptor_loss	1.0000
16:89959106:GT:G	donor_gain	1.0000
16:89960930:GGGT:G	acceptor_gain	1.0000
16:89961094:GC:G	donor_gain	1.0000
16:89961096:G:GG	donor_gain	1.0000
16:89961735:AGGG:A	acceptor_gain	1.0000
16:89961736:GGGG:G	acceptor_gain	1.0000
16:89961847:GACTT:G	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000191432 (16:89948245 TA>T,TAA), RS1000221192 (16:89947996 G>A,C), RS1000236327 (16:89965635 G>A), RS1000312505 (16:89965467 G>A,C,T), RS1000403224 (16:89952085 G>C), RS1000799273 (16:89955879 T>A), RS1000973497 (16:89957969 C>G,T), RS1001026075 (16:89957720 T>C), RS1001242453 (16:89964655 G>C), RS1001661351 (16:89955844 G>A), RS1001721618 (16:89960387 T>C), RS1001934997 (16:89968401 G>A,C,T), RS1001946770 (16:89952119 C>T), RS1001977116 (16:89956815 G>A,T), RS1001987790 (16:89947456 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST003327_5	Squamous cell carcinoma	2.000000e-44
GCST003422_1	Squamous cell carcinoma	2.000000e-09
GCST005897_1	Low tan response	2.000000e-35
GCST006986_24	Red vs. brown/black hair color	4.000000e-11
GCST006986_38	Red vs. brown/black hair color	2.000000e-56
GCST006986_4	Red vs. brown/black hair color	4.000000e-25
GCST006989_52	Brown vs. black hair color	8.000000e-28
GCST008870_82	Keratinocyte cancer (MTAG)	7.000000e-22
GCST010703_280	Brain morphology (MOSTest)	2.000000e-15
GCST011100_21	Aging traits (healthspan, parental lifespan or longevity) (multivariate analysis)	7.000000e-12
GCST012227_386	Hip circumference adjusted for BMI	2.000000e-09
GCST90013410_55	Basal cell carcinoma	1.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004279	suntan
EFO:0003924	hair color
EFO:0010176	keratinocyte carcinoma
EFO:0004346	neuroimaging measurement
EFO:0007796	parental longevity
EFO:0009762	healthspan
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, increases expression, decreases expression	3
Benzo(a)pyrene	affects methylation, increases methylation	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
nickel sulfate	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
Decitabine	affects expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Calcitriol	increases expression	1
Cisplatin	affects expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Diethylhexyl Phthalate	increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	increases expression	1
Methapyrilene	increases methylation	1
Ozone	increases abundance, affects expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

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