SP8

Summary

SP8 (Sp8 transcription factor, HGNC:19196) is a protein-coding gene on chromosome 7p21.1, encoding Transcription factor Sp8 (Q8IXZ3). Transcription factor which plays a key role in limb development.

The protein encoded by this gene is an SP family transcription factor that in mouse has been shown to be essential for proper limb development. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 221833 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 97 total
• MANE Select transcript: NM_182700

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19196
Approved symbol	SP8
Name	Sp8 transcription factor
Location	7p21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164651
Ensembl biotype	protein_coding
OMIM	608306
Entrez	221833

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000361443, ENST00000418710

RefSeq mRNA: 2 — MANE Select: NM_182700 NM_182700, NM_198956

CCDS: CCDS43555, CCDS5372

Canonical transcript exons

ENST00000418710 — 2 exons

Exon	Start	End
ENSE00003471433	20782279	20785795
ENSE00003488541	20786778	20786886

Expression profiles

Bgee: expression breadth broad, 76 present calls, max score 98.38.

FANTOM5 (CAGE): breadth broad, TPM avg 3.1081 / max 378.2798, expressed in 247 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83022	1.2405	123
83025	0.7555	205
83024	0.4021	128
83023	0.2367	57
83020	0.1171	69
83016	0.0812	45
83018	0.0775	37
83017	0.0700	32
83021	0.0697	34
83019	0.0446	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	98.38	gold quality
sural nerve	UBERON:0015488	92.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.71	silver quality
epithelial cell of pancreas	CL:0000083	84.38	silver quality
ventricular zone	UBERON:0003053	83.70	gold quality
upper arm skin	UBERON:0004263	82.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.86	gold quality
nasal cavity mucosa	UBERON:0001826	78.92	gold quality
ganglionic eminence	UBERON:0004023	78.32	gold quality
kidney epithelium	UBERON:0004819	77.81	gold quality
nasal cavity epithelium	UBERON:0005384	74.49	silver quality
mucosa of paranasal sinus	UBERON:0005030	74.20	gold quality
tibialis anterior	UBERON:0001385	73.69	silver quality
buccal mucosa cell	CL:0002336	73.22	gold quality
cardiac muscle of right atrium	UBERON:0003379	68.71	gold quality
hindlimb stylopod muscle	UBERON:0004252	68.50	gold quality
left ventricle myocardium	UBERON:0006566	68.46	gold quality
prostate gland	UBERON:0002367	67.30	gold quality
endothelial cell	CL:0000115	67.17	gold quality
oocyte	CL:0000023	64.13	gold quality
sperm	CL:0000019	62.99	gold quality
deltoid	UBERON:0001476	62.81	gold quality
ileal mucosa	UBERON:0000331	61.87	gold quality
epithelium of nasopharynx	UBERON:0001951	61.57	gold quality
cortical plate	UBERON:0005343	60.34	gold quality
layer of synovial tissue	UBERON:0007616	60.34	gold quality
skin of hip	UBERON:0001554	59.31	silver quality
parotid gland	UBERON:0001831	59.28	gold quality
myocardium	UBERON:0002349	58.54	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	126.72
E-ANND-3	no	1.80

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
FGF8	Activation
PAX6	Unknown

JASPAR motifs

Motif	Name	Family
MA0747.1	SP8	Three-zinc finger Kruppel-related
MA0747.2	SP8	Three-zinc finger Kruppel-related

JASPAR matrix evidence (PMIDs): PMID:23019068

Upstream regulators (CollecTRI, top): EMX2

miRNA regulators (miRDB)

152 targeting SP8, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-LET-7D-5P	99.96	71.76	1632

Literature-anchored findings (GeneRIF, showing 3)

• This study provided that SP8 are associated with Bipolar I in the Han Chinese population (PMID:20386566)
• Genetic variants on 3q21 and in the Sp8 transcription factor gene (SP8) as susceptibility loci for psychotic disorders. (PMID:23967141)
• Data suggest expression of transcription factor p8/SP8 is up-regulated in endoplasmic reticulum stress due to lipotoxicity; overexpression of SP8 up-regulates autophagy; autophagy due to lipotoxicity requires SP8; these reactions are mTOR-independent. (PMID:26733200)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sp8b	ENSDARG00000056666
mus_musculus	Sp8	ENSMUSG00000048562
rattus_norvegicus	Sp8	ENSRNOG00000068174
drosophila_melanogaster	luna	FBGN0040765

Paralogs (22): KLF6 (ENSG00000067082), KLF8 (ENSG00000102349), KLF5 (ENSG00000102554), KLF1 (ENSG00000105610), KLF3 (ENSG00000109787), KLF7 (ENSG00000118263), KLF12 (ENSG00000118922), KLF9 (ENSG00000119138), KLF2 (ENSG00000127528), KLF16 (ENSG00000129911), KLF4 (ENSG00000136826), KLF10 (ENSG00000155090), KLF15 (ENSG00000163884), KLF13 (ENSG00000169926), SP7 (ENSG00000170374), KLF17 (ENSG00000171872), KLF11 (ENSG00000172059), SP6 (ENSG00000189120), SP5 (ENSG00000204335), SP9 (ENSG00000217236), KLF14 (ENSG00000266265), KLF18 (ENSG00000283039)

Protein

Protein identifiers

Transcription factor Sp8 — Q8IXZ3 (reviewed: Q8IXZ3)

Alternative names: Specificity protein 8

All UniProt accessions (1): Q8IXZ3

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor which plays a key role in limb development. Positively regulates FGF8 expression in the apical ectodermal ridge (AER) and contributes to limb outgrowth in embryos.

Subcellular location. Nucleus.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

Similarity. Belongs to the Sp1 C2H2-type zinc-finger protein family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8IXZ3-3	3	yes
Q8IXZ3-1	1
Q8IXZ3-2	2
Q8IXZ3-4	4, Sp8L

RefSeq proteins (2): NP_874359, NP_945194 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (18 total): compositionally biased region 5, region of interest 4, zinc finger region 3, splice variant 3, chain 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IXZ3-F1	48.24	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 139 (showing top): TGACCTY_ERR1_Q2, LHX3_01, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, TCF4_Q5, GOBP_PROXIMAL_DISTAL_PATTERN_FORMATION, GOBP_APPENDAGE_DEVELOPMENT, HNF4_01, MAF_Q6, HNF1_C, GFI1_01, LEF1_Q6, GOBP_EMBRYO_DEVELOPMENT, CTTTGTA_MIR524, RAAGNYNNCTTY_UNKNOWN, TAATTA_CHX10_01

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), dorsal/ventral pattern formation (GO:0009953), proximal/distal pattern formation (GO:0009954), embryonic limb morphogenesis (GO:0030326)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), zinc ion binding (GO:0008270), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regionalization	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transition metal ion binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
DNA binding	1
cation binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

796 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SP8	CALB2	P22676	863
SP8	DNAH11	Q96DT5	778
SP8	EMX2	Q04743	731
SP8	WNT3	P56703	689
SP8	ACRV1	P26436	662
SP8	GSX2	Q9BZM3	621
SP8	DLX2	Q07687	592
SP8	SHH	Q15465	587
SP8	NR2F1	P10589	584
SP8	PAX6	P26367	576
SP8	FGF10	O15520	573
SP8	BMPR1A	P36894	537
SP8	FGF17	O60258	489
SP8	LHX2	P50458	487
SP8	EMX1	Q04741	485

IntAct

5 interactions, top by confidence:

A	B	Type	Score
SDCBP	SP8	psi-mi:“MI:0407”(direct interaction)	0.440
ZNF273	SP8	psi-mi:“MI:0915”(physical association)	0.370
ZNF519	SP8	psi-mi:“MI:0915”(physical association)	0.370
HEYL	SP8	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (5): SP8 (Proximity Label-MS), SP8 (Proximity Label-MS), SP8 (Two-hybrid), SP8 (Two-hybrid), SP8 (Two-hybrid)

ESM2 similar proteins: A0JC51, G3V7L5, O57311, O57401, O60481, O73689, O77215, O95409, P07247, P0CG40, P17208, P20264, P20266, P23441, P23769, P28166, P31361, P32027, P39768, P43698, P43699, P46152, P46684, P50220, Q01851, Q04649, Q08369, Q0VGT2, Q12837, Q15915, Q24573, Q5XGT8, Q62520, Q62521, Q63262, Q63934, Q64HY3, Q6DJQ6, Q7TQ40, Q8BMJ8

Diamond homologs: A5ABV9, O08876, O14901, O70494, O89090, O89091, P08047, P0CG40, P41696, Q01714, Q02446, Q02447, Q0VA40, Q13351, Q22678, Q3SY56, Q5XGT8, Q62445, Q64HY3, Q64HY5, Q6BEB4, Q6NW96, Q6P0J3, Q8BMJ8, Q8IXZ3, Q8K1S5, Q8TDD2, Q8VI67, Q90WR8, Q9ESX2, Q9JHX2, Q9TZ64, A1C6L9, A1DH89, A2QCJ9, B0XSK6, B8NGC8, G4N3L5, K9GKQ6, O14335

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	25
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

317 predictions. Top by Δscore:

Variant	Effect	Δscore
7:20786776:ACC:A	donor_gain	0.9900
7:20786777:CCC:C	donor_gain	0.9900
7:20786776:AC:A	donor_gain	0.9800
7:20786777:CC:C	donor_gain	0.9800
7:20786770:AGACT:A	donor_loss	0.9700
7:20786771:GACTC:G	donor_loss	0.9700
7:20786772:ACT:A	donor_loss	0.9700
7:20786773:CT:C	donor_loss	0.9700
7:20786774:TCA:T	donor_loss	0.9700
7:20786775:C:CA	donor_loss	0.9700
7:20786776:A:C	donor_loss	0.9700
7:20786777:C:A	donor_loss	0.9700
7:20786769:GAGAC:G	donor_loss	0.9600
7:20786776:A:AC	donor_gain	0.9500
7:20786777:C:CC	donor_gain	0.9500
7:20785792:CTTC:C	acceptor_gain	0.9300
7:20785793:TTCC:T	acceptor_loss	0.9100
7:20785795:CCTG:C	acceptor_loss	0.9100
7:20785796:CTGCG:C	acceptor_loss	0.9100
7:20785847:G:T	acceptor_gain	0.9000
7:20785796:C:CC	acceptor_gain	0.8900
7:20786777:CCCCT:C	donor_gain	0.8500
7:20785793:TTC:T	acceptor_gain	0.8300
7:20785800:G:T	acceptor_gain	0.8100
7:20786776:ACCC:A	donor_gain	0.8100
7:20786777:CCCC:C	donor_gain	0.8100
7:20785799:C:CT	acceptor_gain	0.7900
7:20786039:CCACG:C	acceptor_gain	0.7800
7:20786040:CACGC:C	acceptor_gain	0.7800
7:20786042:CG:C	acceptor_gain	0.7700

AlphaMissense

3253 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:20784461:G:C	H434Q	1.000
7:20784461:G:T	H434Q	1.000
7:20784462:T:C	H434R	1.000
7:20784463:G:C	H434D	1.000
7:20784463:G:T	H434N	1.000
7:20784471:A:G	L431P	1.000
7:20784477:T:A	D429V	1.000
7:20784484:G:T	R427S	1.000
7:20784488:G:C	F425L	1.000
7:20784488:G:T	F425L	1.000
7:20784489:A:C	F425C	1.000
7:20784489:A:G	F425S	1.000
7:20784490:A:G	F425L	1.000
7:20784494:C:A	K423N	1.000
7:20784494:C:G	K423N	1.000
7:20784500:G:C	C421W	1.000
7:20784501:C:G	C421S	1.000
7:20784501:C:T	C421Y	1.000
7:20784502:A:G	C421R	1.000
7:20784502:A:T	C421S	1.000
7:20784509:A:C	C418W	1.000
7:20784510:C:G	C418S	1.000
7:20784510:C:T	C418Y	1.000
7:20784511:A:G	C418R	1.000
7:20784511:A:T	C418S	1.000
7:20784515:G:C	F416L	1.000
7:20784515:G:T	F416L	1.000
7:20784516:A:G	F416S	1.000
7:20784517:A:G	F416L	1.000
7:20784533:G:C	H410Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000251075 (7:20785133 C>G,T), RS1000989047 (7:20783785 G>A,C,T), RS1001058278 (7:20783534 A>C,T), RS1001677623 (7:20782712 C>G,T), RS1001766025 (7:20788793 T>C,G), RS1001817070 (7:20788403 T>C), RS1002049983 (7:20783477 G>A), RS1002150527 (7:20787029 T>A,C,G), RS1003130183 (7:20788324 G>A), RS1003589800 (7:20788778 G>A,T), RS1003719621 (7:20782006 T>A), RS1003769533 (7:20785975 G>A), RS1005603927 (7:20788860 G>T), RS1005793188 (7:20783241 T>C), RS1005957229 (7:20787292 A>G)

Disease associations

OMIM: gene MIM:608306 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000635_9	Response to statin therapy	7.000000e-06
GCST000654_2	Bipolar I disorder	5.000000e-07
GCST001942_12	Prostate cancer	5.000000e-13
GCST005956_25	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST005962_47	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	7.000000e-07
GCST007328_47	Alcohol consumption (drinks per week)	2.000000e-08
GCST008476_4	Emphysema annual change measurement in smokers (percent low attenuation area)	1.000000e-06
GCST009798_31	Asthma	2.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007626	emphysema imaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, decreases expression	7
trichostatin A	affects cotreatment, decreases expression, increases expression	4
entinostat	decreases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	affects expression, decreases expression	2
methylmercuric chloride	decreases expression	1
cupric chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Vorinostat	decreases expression	1
Panobinostat	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	decreases reaction, increases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A6P4	SEES3-1V human SP8, clone1	Embryonic stem cell	Male
CVCL_A6P5	SEES3-1V human SP8, clone2	Embryonic stem cell	Male
CVCL_A6P6	SEES3-1V human SP8, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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