SPAG8

Summary

SPAG8 (sperm associated antigen 8, HGNC:14105) is a protein-coding gene on chromosome 9p13.3, encoding Sperm-associated antigen 8 (Q99932). Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.

The correlation of anti-sperm antibodies with cases of unexplained infertility implicates a role for these antibodies in blocking fertilization. Improved diagnosis and treatment of immunologic infertility, as well as identification of proteins for targeted contraception, are dependent on the identification and characterization of relevant sperm antigens. The protein encoded by this gene is recognized by sperm agglutinating antibodies from an infertile woman. This protein is localized in germ cells of the testis at all stages of spermatogenesis and is localized to the acrosomal region of mature spermatozoa. This protein interacts with ACT (activator of CREM in testis) and may play a role in CREM (cAMP response element modulator)-ACT-mediated gene transcription during spermatogenesis. This protein may also play a role in spermatogenesis by regulating microtubule formation and cell division. Alternatively spliced variants that encode different protein isoforms have been described but the full-length sequences of only two have been determined.

Source: NCBI Gene 26206 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 107 total
• MANE Select transcript: NM_001039592

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14105
Approved symbol	SPAG8
Name	sperm associated antigen 8
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	hSMP-1, HSD-1, BS-84, SPAG3, CT142
Ensembl gene	ENSG00000137098
Ensembl biotype	protein_coding
OMIM	605731
Entrez	26206

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000340291, ENST00000396638, ENST00000460836, ENST00000463889, ENST00000471631, ENST00000472605, ENST00000475644, ENST00000479751, ENST00000484764, ENST00000489063, ENST00000495667, ENST00000497810, ENST00000871850, ENST00000871851

RefSeq mRNA: 3 — MANE Select: NM_001039592 NM_001039592, NM_001366760, NM_172312

CCDS: CCDS43798, CCDS6592

Canonical transcript exons

ENST00000396638 — 7 exons

Exon	Start	End
ENSE00000699496	35811182	35812001
ENSE00001317780	35812104	35812262
ENSE00001921541	35809795	35810132
ENSE00003487039	35810637	35810682
ENSE00003490394	35810439	35810553
ENSE00003518380	35810883	35811057
ENSE00003605148	35810247	35810309

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 99.43.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9912 / max 133.6895, expressed in 637 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100661	1.0517	270
100662	0.9395	439

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.43	gold quality
tendon of biceps brachii	UBERON:0008188	93.84	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.28	gold quality
left testis	UBERON:0004533	92.09	gold quality
right testis	UBERON:0004534	91.79	gold quality
bronchial epithelial cell	CL:0002328	91.19	gold quality
epithelium of bronchus	UBERON:0002031	90.86	gold quality
testis	UBERON:0000473	90.31	gold quality
bronchus	UBERON:0002185	90.08	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.71	gold quality
choroid plexus epithelium	UBERON:0003911	87.48	gold quality
adenohypophysis	UBERON:0002196	86.66	gold quality
buccal mucosa cell	CL:0002336	86.08	silver quality
pituitary gland	UBERON:0000007	85.64	gold quality
left uterine tube	UBERON:0001303	84.82	gold quality
olfactory bulb	UBERON:0002264	84.73	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.78	gold quality
fallopian tube	UBERON:0003889	83.73	gold quality
type B pancreatic cell	CL:0000169	82.64	gold quality
right lobe of thyroid gland	UBERON:0001119	82.28	gold quality
right lung	UBERON:0002167	82.15	gold quality
diaphragm	UBERON:0001103	82.11	silver quality
caudate nucleus	UBERON:0001873	82.00	gold quality
left lobe of thyroid gland	UBERON:0001120	81.35	gold quality
thyroid gland	UBERON:0002046	81.27	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.18	gold quality
epithelium of nasopharynx	UBERON:0001951	81.08	gold quality
apex of heart	UBERON:0002098	80.91	gold quality
endocervix	UBERON:0000458	80.82	gold quality
nasal cavity mucosa	UBERON:0001826	80.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.98

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• The antibody of this recombinant protein inhibits the mouse acrosome reaction and prmits mouse sperm-zona pellucida binding. (PMID:17187156)
• Sperm associated antigen 8 might be involved in the regulation of cell cycle by changing the phosphorylation level of Tyr15 on CDC2 Protein Kinase. (PMID:19548270)
• Results indicate that SPAG8 acts as a regulator of ACT and plays an important role in CREM-ACT-mediated gene transcription during spermatogenesis. (PMID:20488182)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	spag8	ENSDARG00000103843
mus_musculus	Spag8	ENSMUSG00000066196
rattus_norvegicus	Spag8	ENSRNOG00000032539

Protein

Protein identifiers

Sperm-associated antigen 8 — Q99932 (reviewed: Q99932)

Alternative names: HSD-1, Sperm membrane protein 1, Sperm membrane protein BS-84

All UniProt accessions (6): A0A140VJV0, C9JAA8, Q99932, F2Z302, F8WBP3, H7C4J6

UniProt curated annotations — full annotation on UniProt →

Function. Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating. Plays a role in spermatogenesis by enhancing the binding of CREM isoform tau to its coactivator FHL5 and increasing the FHL5-regulated transcriptional activation of CREM isoform tau. Involved in the acrosome reaction and in binding of sperm to the zona pellucida. Plays a role in regulation of the cell cycle by controlling progression through the G2/M phase, possibly by delaying the activation of CDK1 which is required for entry into mitosis. May play a role in fertility and microtubule formation through interaction with RANBP9.

Subunit / interactions. Microtubule inner protein component of sperm flagellar doublet microtubules. Interacts with FHL5 (via second LIM domain). Interacts with RANBP9.

Subcellular location. Cytoplasm. Nucleus. Cytoplasmic vesicle. Secretory vesicle. Acrosome. Cytoskeleton. Microtubule organizing center. Spindle. Cilium axoneme. Flagellum axoneme.

Tissue specificity. Expressed in testis (germ cells), but not in liver, kidney, prostate and small intestine. Expressed in airway epithelial cells.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the SPAG8 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99932-3	3	yes
Q99932-1	1
Q99932-2	2

RefSeq proteins (3): NP_001034681, NP_001353689, NP_758516 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026124	Sperm-assoc_Ag8	Family

Pfam: PF22584

UniProt features (20 total): sequence conflict 7, region of interest 5, splice variant 3, sequence variant 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7UNG	ELECTRON MICROSCOPY	3.6
8J07	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99932-F1	57.79	0.05

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 110 (showing top): GOBP_SINGLE_FERTILIZATION, TGCGCANK_UNKNOWN, GOCC_SECRETORY_GRANULE, TGACCTY_ERR1_Q2, GOBP_MALE_GAMETE_GENERATION, GOCC_MICROTUBULE_ORGANIZING_CENTER, WCTCNATGGY_UNKNOWN, GOBP_CILIUM_MOVEMENT, chr9p13, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, MORF_EPHA7, MORF_RAB3A, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, MORF_WNT1, GOBP_FERTILIZATION

GO Biological Process (5): spermatogenesis (GO:0007283), single fertilization (GO:0007338), cell differentiation (GO:0030154), flagellated sperm motility (GO:0030317), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (2): microtubule binding (GO:0008017), protein binding (GO:0005515)

GO Cellular Component (19): acrosomal vesicle (GO:0001669), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), microtubule organizing center (GO:0005815), spindle (GO:0005819), cytosol (GO:0005829), axonemal microtubule (GO:0005879), cilium (GO:0005929), membrane (GO:0016020), sperm flagellum (GO:0036126), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), axonemal A tubule inner sheath (GO:0160111), cytoskeleton (GO:0005856), cytoplasmic vesicle (GO:0031410), motile cilium (GO:0031514), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	9
microtubule cytoskeleton	2
intracellular membraneless organelle	2
cytoplasm	2
sperm flagellum	2
developmental process involved in reproduction	1
male gamete generation	1
fertilization	1
cellular developmental process	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
tubulin binding	1
binding	1
secretory granule	1
germ cell nucleus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasmic microtubule	1
axoneme	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
9+2 motile cilium	1
A axonemal microtubule	1
axonemal microtubule doublet inner sheath	1
intracellular vesicle	1
cilium	1

Protein interactions and networks

STRING

1034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPAG8	SPAG17	Q6Q759	654
SPAG8	FBXO39	Q8N4B4	609
SPAG8	SPAG16	Q8N0X2	570
SPAG8	TMEM8B	A6NDV4	530
SPAG8	SPAG6	O75602	505
SPAG8	CFAP126	Q5VTH2	474
SPAG8	SPAG5	Q96R06	467
SPAG8	HINT2	Q9BX68	461
SPAG8	SLC14A2	Q15849	449
SPAG8	CIMAP1A	Q96PU9	447
SPAG8	ACSM3	Q53FZ2	437
SPAG8	FAM221B	A6H8Z2	433
SPAG8	YJU2B	P13994	428
SPAG8	SPEF2	Q9C093	420
SPAG8	RPAP3	Q9H6T3	417

IntAct

23 interactions, top by confidence:

A	B	Type	Score
CSTF2	SPAG8	psi-mi:“MI:0915”(physical association)	0.560
SNRPC	SPAG8	psi-mi:“MI:0915”(physical association)	0.560
KLHL32	SPAG8	psi-mi:“MI:0915”(physical association)	0.560
DTX2	SPAG8	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	SNRPC	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	KLHL32	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	DTX2	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	CSTF2	psi-mi:“MI:0915”(physical association)	0.560
ECE1	SPAG8	psi-mi:“MI:0915”(physical association)	0.370
SPAG8	NSD3	psi-mi:“MI:0915”(physical association)	0.370
SPAG8	KDM3B	psi-mi:“MI:0915”(physical association)	0.370
JMJD4	SPAG8	psi-mi:“MI:0915”(physical association)	0.370
CARM1	SPAG8	psi-mi:“MI:0915”(physical association)	0.370
SPAG8	PRMT5	psi-mi:“MI:0915”(physical association)	0.370
PRMT2	SPAG8	psi-mi:“MI:0915”(physical association)	0.370
SPAG8	PRMT1	psi-mi:“MI:0915”(physical association)	0.370
UBQLN4	SPAG8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (94): SPAG8 (Two-hybrid), SPAG8 (Two-hybrid), DTX2 (Two-hybrid), KLHL32 (Two-hybrid), SPAG8 (Affinity Capture-MS), SPAG8 (Synthetic Lethality), SPAG8 (Two-hybrid), SPAG8 (Two-hybrid), SPAG8 (Two-hybrid), SPAG8 (Two-hybrid), SPAG8 (Two-hybrid), SPAG8 (Two-hybrid), SPAG8 (Two-hybrid), SPAG8 (Two-hybrid), SPAG8 (Two-hybrid)

ESM2 similar proteins: A0A1B0GTD5, A0A1B0GTJ6, A0A1B0GUX0, A0A3Q1MT14, A0JNL1, A5PJD8, B9EJX3, E1B9R1, E1BNS6, F1MMV1, Q0P591, Q148A4, Q14BB9, Q1JPL0, Q2KJ10, Q2MH31, Q2T9T0, Q2TA11, Q32L72, Q32L77, Q3V0Q6, Q5BN46, Q5PQN4, Q5RBH3, Q5RHU7, Q5SPV6, Q5SVJ3, Q5VTT2, Q5VZQ5, Q66HR9, Q6AYM0, Q7Z5V6, Q8CDU5, Q8N5S3, Q8N865, Q8NA69, Q8NCR6, Q8NEG2, Q95LU0, Q96K30

Diamond homologs: E1BNS6, Q3V0Q6, Q99932

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	86
Likely benign	7
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

1204 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35808656:C:G	donor_gain	1.0000
9:35808807:T:TA	acceptor_gain	1.0000
9:35809123:A:AG	acceptor_gain	1.0000
9:35808505:TCAGG:T	acceptor_loss	0.9900
9:35808506:CAG:C	acceptor_loss	0.9900
9:35808507:A:AC	acceptor_loss	0.9900
9:35808661:GC:G	donor_gain	0.9900
9:35808808:G:A	acceptor_gain	0.9900
9:35809124:T:G	acceptor_gain	0.9900
9:35809128:A:AG	acceptor_gain	0.9900
9:35809129:C:G	acceptor_gain	0.9900
9:35809132:T:G	acceptor_gain	0.9900
9:35809145:A:AG	acceptor_gain	0.9900
9:35809146:C:G	acceptor_gain	0.9900
9:35809149:A:AG	acceptor_gain	0.9900
9:35809154:A:AG	acceptor_gain	0.9900
9:35809155:G:GA	acceptor_gain	0.9900
9:35809155:GC:G	acceptor_gain	0.9900
9:35809203:C:G	donor_gain	0.9900
9:35809378:A:AG	acceptor_gain	0.9900
9:35809379:G:GG	acceptor_gain	0.9900
9:35812075:ATG:A	donor_gain	0.9900
9:35812102:A:AC	donor_gain	0.9900
9:35812103:C:CC	donor_gain	0.9900
9:35812125:T:TA	donor_gain	0.9900
9:35808683:GGTAA:G	donor_loss	0.9800
9:35808684:G:GT	donor_loss	0.9800
9:35808685:TAAG:T	donor_loss	0.9800
9:35808749:TCAAA:T	acceptor_loss	0.9800
9:35808750:CAAA:C	acceptor_loss	0.9800

AlphaMissense

3111 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35810079:G:C	F439L	0.989
9:35810079:G:T	F439L	0.989
9:35810081:A:G	F439L	0.989
9:35810273:A:G	W413R	0.985
9:35810273:A:T	W413R	0.985
9:35810274:G:C	F412L	0.983
9:35810274:G:T	F412L	0.983
9:35810276:A:G	F412L	0.983
9:35810097:G:C	F433L	0.981
9:35810097:G:T	F433L	0.981
9:35810099:A:G	F433L	0.981
9:35811191:C:A	W285C	0.980
9:35811191:C:G	W285C	0.980
9:35810271:C:A	W413C	0.979
9:35810271:C:G	W413C	0.979
9:35811193:A:G	W285R	0.965
9:35811193:A:T	W285R	0.965
9:35810091:C:A	K435N	0.955
9:35810091:C:G	K435N	0.955
9:35810098:A:G	F433S	0.955
9:35810677:G:T	R349S	0.955
9:35811054:C:G	A290P	0.951
9:35810095:C:G	R434P	0.949
9:35811194:G:C	N284K	0.948
9:35811194:G:T	N284K	0.948
9:35810080:A:G	F439S	0.946
9:35810098:A:C	F433C	0.945
9:35810272:C:G	W413S	0.943
9:35810082:G:C	S438R	0.941
9:35810082:G:T	S438R	0.941

dbSNP variants (sampled 300 via entrez): RS1000949573 (9:35812234 T>C), RS1001285126 (9:35812685 C>G,T), RS1001567843 (9:35813021 CAG>C), RS1002101422 (9:35807890 C>T), RS1003458073 (9:35809806 G>A,T), RS1003512502 (9:35813967 G>A,C), RS1003972227 (9:35807801 G>C), RS1004149595 (9:35814145 A>G), RS1004424338 (9:35807478 C>T), RS1004592059 (9:35812874 G>A,T), RS1005515984 (9:35811327 T>C), RS1005853357 (9:35812409 C>A,T), RS1008216294 (9:35811865 T>C), RS1008744798 (9:35809739 G>A,T), RS1008770248 (9:35813274 T>A)

Disease associations

OMIM: gene MIM:605731 | disease phenotypes: MIM:602875, MIM:615923, MIM:617116, MIM:616255

GenCC curated gene-disease

Mondo (4): acromesomelic dysplasia 1, Maroteaux type (MONDO:0011275), tall stature-scoliosis-macrodactyly of the great toes syndrome (MONDO:0014401), epilepsy, familial focal, with variable foci 2 (MONDO:0014924), short stature with nonspecific skeletal abnormalities (MONDO:0975810)

Orphanet (2): Tall stature-long halluces-multiple extra-epiphyses syndrome (Orphanet:329191), Acromesomelic dysplasia, Maroteaux type (Orphanet:40)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_52	Brain morphology (MOSTest)	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535661	Acromesomelic dysplasia, Maroteaux type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	1
CGP 52608	increases reaction, affects binding	1
jinfukang	affects cotreatment, increases expression	1
NSC668394	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Amphotericin B	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Polychlorinated Biphenyls	affects expression	1
Smoke	increases expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	decreases methylation	1
beta-Naphthoflavone	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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