F8A1

Summary

F8A1 (coagulation factor VIII associated 1, HGNC:3547) is a protein-coding gene on chromosome Xq28, encoding 40-kDa huntingtin-associated protein (P23610). RAB5A effector molecule that is involved in vesicular trafficking of early endosomes.

This gene is contained entirely within intron 22 of the factor VIII gene; spans less than 2 kb, and is transcribed in the direction opposite of factor VIII. A portion of intron 22 (int22h), containing F8A, is repeated twice extragenically closer to the Xq telomere. Although its function is unknown, the observation that this gene is conserved in the mouse implies it has some function. Unlike factor VIII, this gene is transcribed abundantly in a wide variety of cell types.

Source: NCBI Gene 8263 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 3 total — 3 pathogenic
• MANE Select transcript: NM_012151

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3547
Approved symbol	F8A1
Name	coagulation factor VIII associated 1
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	DXS522E
Ensembl gene	ENSG00000288722
Ensembl biotype	protein_coding
OMIM	305423
Entrez	8263

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000610495

RefSeq mRNA: 1 — MANE Select: NM_012151 NM_012151

CCDS: CCDS35459

Canonical transcript exons

ENST00000610495 — 1 exons

Exon	Start	End
ENSE00003730703	154886355	154888061

Expression profiles

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0347 / max 5.7034, expressed in 14 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198209	0.0347	14

Top tissues by expression

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting F8A1, 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-4533	100.00	69.48	2758
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-2681-3P	98.18	65.28	577
HSA-MIR-4446-3P	97.91	64.29	991
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-4678	97.59	68.31	902
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656
HSA-MIR-4714-5P	97.04	67.76	955
HSA-MIR-490-5P	96.75	65.81	661
HSA-MIR-2909	96.36	67.30	562
HSA-MIR-139-3P	95.24	63.10	316
HSA-MIR-6802-5P	94.94	65.95	366
HSA-MIR-6820-5P	94.04	61.13	161
HSA-MIR-1973	93.96	64.98	81

Literature-anchored findings (GeneRIF, showing 9)

• The mutation Arg489Ala/Arg490Ala/Lys493Ala (489-3A) possessed near-normal affinity for FIXa and showed no effect on the Km for Factor X. (PMID:15009463)
• cupredoxin-like A1 subdomains in fVIII contain inter-species differences that are a result of selective pressure on the dissociation rate constant (PMID:16513639)
• analysis of the residues contributing to A2 domain-dependent structural stability in factor VIII and factor VIIIa (PMID:18299331)
• Protein S enhances the tissue factor pathway inhibitor inhibition of factor Xa but not its inhibition of factor VIIa-tissue factor (PMID:18419747)
• Orientations for FVIIIa are identified that bind to the membrane surface and support a new interaction between the A3 domain and the membrane, probably mediated in part by Arg(1719) and Arg(1721) (PMID:23521092)
• Pathological polyQ expansion does not alter the conformation of the Huntingtin-HAP40 complex. (PMID:33909994)
• HAP40 protein levels are huntingtin-dependent and decrease in Huntington disease. (PMID:34390835)
• HAP40 is a conserved central regulator of Huntingtin and a potential modulator of Huntington’s disease pathogenesis. (PMID:35853002)
• Huntingtin and Its Partner Huntingtin-Associated Protein 40: Structural and Functional Considerations in Health and Disease. (PMID:35871360)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	f8a	ENSDARG00000025518
mus_musculus	F8a	ENSMUSG00000078317
rattus_norvegicus	F8a1	ENSRNOG00000080664
rattus_norvegicus		ENSRNOG00000085632
drosophila_melanogaster	Hap40	FBGN0030671

Paralogs (2): F8A3 (ENSG00000277150), F8A2 (ENSG00000288709)

Protein

Protein identifiers

40-kDa huntingtin-associated protein — P23610 (reviewed: P23610)

Alternative names: CpG island protein, Factor VIII intron 22 protein

All UniProt accessions (1): P23610

UniProt curated annotations — full annotation on UniProt →

Function. RAB5A effector molecule that is involved in vesicular trafficking of early endosomes. Mediates the recruitment of HTT by RAB5A onto early endosomes. The HTT-F8A1/F8A2/F8A3-RAB5A complex stimulates early endosomal interaction with actin filaments and inhibits interaction with microtubules, leading to the reduction of endosome motility.

Subunit / interactions. Interacts with HTT (via C-terminus). Interacts with RAB5A. Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A onto early endosomes.

Subcellular location. Cytoplasm. Nucleus. Early endosome. Nuclear body.

Tissue specificity. Produced abundantly in a wide variety of cell types.

Disease relevance. Up-regulated in brain tissue from patients affected by Huntington’s disease (at protein level). In a Huntington’s disease mouse model overexpression of F8A1/F8A2/F8A3 impairs proteasome activity leading to the accumulation of mutant HTT and causes defective mitochondrial functions.

RefSeq proteins (1): NP_036283* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR039494	F8A	Family

UniProt features (27 total): helix 13, turn 3, strand 3, compositionally biased region 2, initiator methionine 1, chain 1, region of interest 1, short sequence motif 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9PMW	ELECTRON MICROSCOPY	2.1
9PN0	ELECTRON MICROSCOPY	2.3
9YR6	ELECTRON MICROSCOPY	2.3
6X9O	ELECTRON MICROSCOPY	2.6
8VLX	ELECTRON MICROSCOPY	2.6
8W15	ELECTRON MICROSCOPY	2.72
8SAH	ELECTRON MICROSCOPY	3.2
7DXJ	ELECTRON MICROSCOPY	3.6
6EZ8	ELECTRON MICROSCOPY	4
7DXK	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23610-F1	78.88	0.42

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 (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 107 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, MORF_MTA1, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_VESICLE_LOCALIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MORF_HDAC2, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOBP_VESICLE_CYTOSKELETAL_TRAFFICKING, GOBP_REGULATION_OF_CATABOLIC_PROCESS, MORF_RAB6A, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (2): vesicle cytoskeletal trafficking (GO:0099518), negative regulation of proteasomal protein catabolic process (GO:1901799)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), early endosome (GO:0005769), nuclear body (GO:0016604), cytoplasm (GO:0005737), endosome (GO:0005768)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeleton-dependent intracellular transport	1
establishment of vesicle localization	1
proteasomal protein catabolic process	1
negative regulation of protein catabolic process	1
regulation of proteasomal protein catabolic process	1
binding	1
intracellular membrane-bounded organelle	1
endosome	1
nucleoplasm	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

308 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
F8A1	HTT	P42858	974
F8A1	RAB5A	P20339	953
F8A1	HAP1	P54257	583
F8A1	APPL1	Q9UKG1	481
F8A1	REPIN1	Q9BWE0	480
F8A1	NAPB	Q9H115	448
F8A1	ANKFY1	Q9P2R3	388
F8A1	RAB11A	P24410	365
F8A1	RAB8A	P24407	360
F8A1	KIF16B	Q96L93	349
F8A1	RBSN	Q9H1K0	348
F8A1	AP2S1	P53680	336
F8A1	NPIPB15	A6NHN6	327
F8A1	CLIC2	O15247	324
F8A1	SPRY3	O43610	323

IntAct

11 interactions, top by confidence:

A	B	Type	Score
F8A1	HTT	psi-mi:“MI:0915”(physical association)	0.780
RAB30	UBB	psi-mi:“MI:0914”(association)	0.530
F8A1	MTNR1A	psi-mi:“MI:0915”(physical association)	0.000
SH3GLB1	F8A1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): F8A1 (Affinity Capture-MS), F8A1 (Two-hybrid), F8A1 (Two-hybrid), F8A1 (Affinity Capture-Western), KPTN (Affinity Capture-MS), RASA2 (Affinity Capture-MS), ITFG2 (Affinity Capture-MS), HTT (Affinity Capture-MS), HTT (Affinity Capture-MS), CLUH (Affinity Capture-MS), ITFG2 (Affinity Capture-MS), F8A1 (Affinity Capture-MS), KPTN (Affinity Capture-MS), F8A1 (Proximity Label-MS), F8A1 (Positive Genetic)

ESM2 similar proteins: A5A779, A6NLP5, A8E7I5, C5IJB0, F1MX48, I3L5V6, M0RDU0, O35465, O95801, P23610, P36915, P36916, P97452, Q00558, Q08602, Q0P5H9, Q14137, Q14318, Q17QX2, Q2TBQ9, Q2YD98, Q3B7U9, Q3SZV0, Q4R588, Q4R8D2, Q5EA80, Q5NVK5, Q5R8E2, Q5RA07, Q5TM59, Q66H45, Q68G30, Q6AY79, Q6IMX7, Q6P597, Q6P9Z4, Q6SZW1, Q7YR35, Q810A3, Q8C3I8

Diamond homologs: M0RDU0, P23610, Q00558

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1808693	GRCh37/hg19 Xq28(chrX:154112020-154617577)x3	Pathogenic
189219	GRCh37/hg19 Xq28(chrX:154124111-154564398)	Pathogenic
4073611	GRCh37/hg19 Xq28(chrX:152788477-155226944)x2	Pathogenic

SpliceAI

166 predictions. Top by Δscore:

Variant	Effect	Δscore
X:154886439:T:TA	donor_gain	0.8700
X:154887109:T:TA	donor_gain	0.6900
X:154886484:T:TA	donor_gain	0.6200
X:154886664:T:TA	donor_gain	0.6100
X:154886449:C:CT	donor_gain	0.5900
X:154886450:T:TT	donor_gain	0.5900
X:154887164:G:GT	donor_gain	0.5500
X:154887031:GC:G	donor_gain	0.5100
X:154887262:G:GT	donor_gain	0.4800
X:154886555:G:GT	donor_gain	0.4600
X:154887096:C:CT	donor_gain	0.4400
X:154887525:A:AG	acceptor_gain	0.4400
X:154887526:G:GG	acceptor_gain	0.4400
X:154887377:G:GT	donor_gain	0.4300
X:154886554:G:GT	donor_gain	0.4200
X:154886868:T:TA	donor_gain	0.3900
X:154887300:A:T	donor_gain	0.3900
X:154887399:TGGAG:T	donor_gain	0.3900
X:154887481:GGGA:G	donor_gain	0.3700
X:154887482:GGAG:G	donor_gain	0.3700
X:154886556:A:T	donor_gain	0.3600
X:154887265:G:GG	donor_gain	0.3600
X:154887264:A:AG	donor_gain	0.3500
X:154887362:C:T	acceptor_gain	0.3500
X:154887371:G:GT	donor_gain	0.3500
X:154887423:C:G	donor_gain	0.3500
X:154886515:C:T	donor_gain	0.3400
X:154887178:CTGCG:C	acceptor_gain	0.3400
X:154887181:CG:C	acceptor_gain	0.3400
X:154887483:G:T	donor_gain	0.3400

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS113683431 (X:154886026 G>C), RS1156675377 (X:154885705 G>A), RS1156739455 (X:154887702 G>A), RS1161609768 (X:154888225 A>G), RS1161854920 (X:154884962 G>T), RS1162012970 (X:154886121 A>G), RS1163080636 (X:154885354 T>G), RS1164349103 (X:154886324 G>A), RS1164639163 (X:154887724 A>G,T), RS1165771279 (X:154888371 G>T), RS1166099089 (X:154885159 G>A), RS1166167895 (X:154886288 C>G,T), RS1166324509 (X:154885500 A>T), RS1166720558 (X:154885829 G>A), RS1166843207 (X:154887133 G>A)

Disease associations

OMIM: gene MIM:305423 | disease phenotypes: MIM:300260

GenCC curated gene-disease

Mondo (1): syndromic X-linked intellectual disability Lubs type (MONDO:0010283)

Orphanet (1): Proximal Xq28 duplication syndrome (Orphanet:1762)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537723	Lubs X-linked mental retardation syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
bisphenol S	decreases expression, affects cotreatment	1
Temozolomide	increases expression	1
Catechin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Phenobarbital	affects expression	1
Piroxicam	decreases expression	1
Silver	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Sodium Selenite	increases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1
Vitamin K 3	affects expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03077308	Not specified	COMPLETED	Rare Diseases Clinical Research Network: Neurophysiological Correlates
NCT06615206	Not specified	RECRUITING	A First-in-Human Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of a Novel CRISPR RNA-editing Therapy in Patients with Mecp2 Duplication Syndrome, a Rare Orphan Disease (HERO)