SPRR1B

Summary

SPRR1B (small proline rich protein 1B, HGNC:11260) is a protein-coding gene on chromosome 1q21.3, encoding Cornifin-B (P22528). Cross-linked envelope protein of keratinocytes. It is a selective cancer dependency (DepMap: 36.5% of cell lines).

The protein encoded by this gene is an envelope protein of keratinocytes. The encoded protein is crosslinked to membrane proteins by transglutaminase, forming an insoluble layer under the plasma membrane. This protein is proline-rich and contains several tandem amino acid repeats.

Source: NCBI Gene 6699 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 23 total — 1 pathogenic
• Cancer dependency (DepMap): dependent in 36.5% of screened cell lines
• MANE Select transcript: NM_003125

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11260
Approved symbol	SPRR1B
Name	small proline rich protein 1B
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	GADD33
Ensembl gene	ENSG00000169469
Ensembl biotype	protein_coding
OMIM	182266
Entrez	6699

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000307098

RefSeq mRNA: 1 — MANE Select: NM_003125 NM_003125

CCDS: CCDS30863

Canonical transcript exons

ENST00000307098 — 2 exons

Exon	Start	End
ENSE00001177142	153031203	153031247
ENSE00001177153	153032327	153032900

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 99.90.

FANTOM5 (CAGE): breadth broad, TPM avg 74.1362 / max 14552.7720, expressed in 263 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5368	73.4866	262
5370	0.1969	39
5373	0.1433	39
5372	0.1344	43
5374	0.0905	35
5371	0.0692	23
5367	0.0152	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amniotic fluid	UBERON:0000173	99.90	gold quality
gingiva	UBERON:0001828	99.89	gold quality
cervix squamous epithelium	UBERON:0006922	99.89	gold quality
lower esophagus mucosa	UBERON:0035834	99.89	gold quality
gingival epithelium	UBERON:0001949	99.87	gold quality
buccal mucosa cell	CL:0002336	99.82	gold quality
penis	UBERON:0000989	99.82	gold quality
mammalian vulva	UBERON:0000997	99.78	gold quality
pharyngeal mucosa	UBERON:0000355	99.74	gold quality
body of tongue	UBERON:0011876	99.73	gold quality
tongue squamous epithelium	UBERON:0006919	99.69	gold quality
cervix epithelium	UBERON:0004801	99.67	gold quality
periodontal ligament	UBERON:0008266	99.51	gold quality
squamous epithelium	UBERON:0006914	99.49	gold quality
esophagus mucosa	UBERON:0002469	99.34	gold quality
esophagus squamous epithelium	UBERON:0006920	99.20	gold quality
oral cavity	UBERON:0000167	98.97	gold quality
skin of abdomen	UBERON:0001416	98.85	gold quality
upper arm skin	UBERON:0004263	98.63	gold quality
tongue	UBERON:0001723	98.62	gold quality
epithelium of esophagus	UBERON:0001976	98.45	gold quality
upper leg skin	UBERON:0004262	98.14	gold quality
nipple	UBERON:0002030	98.05	gold quality
zone of skin	UBERON:0000014	97.88	gold quality
skin of leg	UBERON:0001511	97.76	gold quality
superior surface of tongue	UBERON:0007371	96.80	gold quality
skin of hip	UBERON:0001554	93.89	gold quality
vagina	UBERON:0000996	92.73	gold quality
hair follicle	UBERON:0002073	87.53	gold quality
esophagus	UBERON:0001043	84.37	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	10158.02
E-CURD-114	yes	1259.34
E-MTAB-10596	no	4470.49
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, EHF, ELF3, FOSL1, FOSL2, JUN, ZEB1

miRNA regulators (miRDB)

20 targeting SPRR1B, 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-574-5P	100.00	66.01	989
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-1245B-3P	98.01	68.91	1387
HSA-MIR-759	96.16	66.77	873
HSA-MIR-6835-5P	95.81	64.27	500

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 36.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• BMK1 (ERK5) regulates squamous differentiation marker SPRR1B transcription in Clara-like H441 cells. (PMID:12091247)
• SPRR1B expression pattern in nonsquamous tumors; findings indicate SPRR1B likely coupled to signals responsible for withdrawal from the proliferative state; overexpression for prolonged periods may disrupt normal progression of mitosis (PMID:12832281)
• SPRR1B is a valid biomarker for the study of the molecular mechanisms of squamous metaplasia. There is a definitive link between inflammation and squamous metaplasia in autoimmune-mediated dry eye disease (PMID:18172072)
• Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families. (PMID:18643845)
• expression of SPRR1B is upregulated in oral CSCs/CICs and SPRR1B has a role in cell growth by suppression of RASSF4 (PMID:23954638)
• Levels SPRR1B proteins were significantly higher in AD skin compared with the levels of these proteins in the skin of healthy subjects. (PMID:27304082)
• Expression of SPRR1 and of SPRR2A is increased in mucosal samples from patients with chronic rhinosinusitis and appeared as a downstream result of TNF alpha modulation, which possibly resulted in epithelial barrier dysfunction. (PMID:28859701)
• Identification of small proline-rich protein 1B (SPRR1B) as a prognostically predictive biomarker for lung adenocarcinoma by integrative bioinformatic analysis. (PMID:33501784)
• Identification of oral squamous cell carcinoma markers MUC2 and SPRR1B downstream of TANGO. (PMID:33620575)
• DGUOK-AS1 promotes cervical squamous cell carcinoma progression by suppressing miR-499a-5p that targets SPRR1B in vitro. (PMID:34808501)

Cross-species orthologs

0 orthologs

Paralogs (20): LCE2B (ENSG00000159455), SPRR2G (ENSG00000159516), LCE3D (ENSG00000163202), SPRR3 (ENSG00000163209), SPRR1A (ENSG00000169474), LCE1D (ENSG00000172155), SPRR4 (ENSG00000184148), LCE3A (ENSG00000185962), LCE3E (ENSG00000185966), LCE5A (ENSG00000186207), LCE1E (ENSG00000186226), LCE2A (ENSG00000187173), LCE2C (ENSG00000187180), LCE2D (ENSG00000187223), LCE3B (ENSG00000187238), KPLCE (ENSG00000198854), PRR9 (ENSG00000203783), LELP1 (ENSG00000203784), LCE1F (ENSG00000240386), LCE3C (ENSG00000244057)

Protein

Protein identifiers

Cornifin-B — P22528 (reviewed: P22528)

Alternative names: 14.9 kDa pancornulin, Small proline-rich protein IB

All UniProt accessions (1): P22528

UniProt curated annotations — full annotation on UniProt →

Function. Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane. Can function as both amine donor and acceptor in transglutaminase-mediated cross-linkage.

Subcellular location. Cytoplasm.

Tissue specificity. Suprabasal layers of squamous-differentiated tissues such as epidermis, esophagus, tongue and trachea.

Post-translational modifications. The N-terminus is blocked.

Induction. By carcinogenic agents and by UV light. During squamous differentiation of epidermal keratinocytes.

Similarity. Belongs to the cornifin (SPRR) family.

RefSeq proteins (1): NP_003116* (*=MANE)

Domains & families (InterPro)

Pfam: PF02389

UniProt features (16 total): repeat 8, sequence variant 4, region of interest 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22528-F1	70.02	0.00

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization

MSigDB gene sets: 92 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, JAEGER_METASTASIS_DN, GOBP_PEPTIDE_CROSS_LINKING, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, NAGASHIMA_NRG1_SIGNALING_UP, CEBPB_01, HINATA_NFKB_TARGETS_KERATINOCYTE_UP, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, MARTINEZ_RB1_TARGETS_UP, RICKMAN_METASTASIS_DN, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, MODULE_298, HUPER_BREAST_BASAL_VS_LUMINAL_UP, TGANTCA_AP1_C, GOBP_EPIDERMIS_DEVELOPMENT

GO Biological Process (4): epidermis development (GO:0008544), peptide cross-linking (GO:0018149), keratinocyte differentiation (GO:0030216), keratinization (GO:0031424)

GO Molecular Function (1): structural molecule activity (GO:0005198)

GO Cellular Component (3): cornified envelope (GO:0001533), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
tissue development	1
protein modification process	1
epidermal cell differentiation	1
skin development	1
keratinocyte differentiation	1
multicellular organismal process	1
molecular_function	1
plasma membrane	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

592 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRR1B	IVL	P07476	903
SPRR1B	TGM1	P22735	869
SPRR1B	LORICRIN	P23490	843
SPRR1B	SPRR2A	P35326	809
SPRR1B	SPRR2D	P22532	802
SPRR1B	SPRR2F	Q96RM1	785
SPRR1B	SPRR2E	P22531	766
SPRR1B	KLK7	P49862	753
SPRR1B	GLIS1	Q8NBF1	726
SPRR1B	SPRR2G	Q9BYE4	725
SPRR1B	S100A10	P08206	717
SPRR1B	C4BPA	P04003	705
SPRR1B	KLK6	Q92876	693
SPRR1B	TCHH	Q07283	622
SPRR1B	FLG	P20930	613

IntAct

40 interactions, top by confidence:

A	B	Type	Score
STAG2	RAD21	psi-mi:“MI:0914”(association)	0.970
L3MBTL2	E2F6	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
MAX	E2F6	psi-mi:“MI:0914”(association)	0.710
ASF1A	HAT1	psi-mi:“MI:0914”(association)	0.640
CBX1	ZNF292	psi-mi:“MI:0914”(association)	0.530
Rab5c	PIP	psi-mi:“MI:0915”(physical association)	0.400
TANK	CNOT1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
ITGA9	IGLL5	psi-mi:“MI:0914”(association)	0.350
KDM4A	PIPSL	psi-mi:“MI:0914”(association)	0.350
POLR2M	MED19	psi-mi:“MI:0914”(association)	0.350
RPAP2	APOC3	psi-mi:“MI:0914”(association)	0.350
SCML2	CSTA	psi-mi:“MI:0914”(association)	0.350
KMT5C	CBX4	psi-mi:“MI:0914”(association)	0.350
TAGLN	LOC392647	psi-mi:“MI:0914”(association)	0.350
ESR2		psi-mi:“MI:0914”(association)	0.350
CFTR	MYH7B	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
ST6GALNAC6	A2ML1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350
LRRC10	A2ML1	psi-mi:“MI:0914”(association)	0.350
GABPA	A2ML1	psi-mi:“MI:0914”(association)	0.350
ST7	A2ML1	psi-mi:“MI:0914”(association)	0.350
SPRR1B	EEF2K	psi-mi:“MI:0914”(association)	0.350

BioGRID (53): SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), KDM4A (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), ASF1A (Affinity Capture-MS), SPRR1B (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTR4, A6QNZ4, O14633, O70554, O70555, O70556, O70557, O70558, O70559, O70560, O70562, P15265, P22528, P22531, P22532, P35321, P35322, P35323, P35324, P35325, P35326, P49901, Q28658, Q32L04, Q4KL71, Q4R956, Q5T5B0, Q5T750, Q5T752, Q5T754, Q5T870, Q5T871, Q5TA76, Q5TA77, Q5TA78, Q5TA79, Q5TA81, Q5TA82, Q5TCM9, Q62266

Diamond homologs: P22528, P35321, P35322, P35323

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EHF	“up-regulates quantity by expression”	SPRR1B	“transcriptional regulation”
ELF3	“up-regulates quantity by expression”	SPRR1B	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	19
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
225520	GRCh37/hg19 1q21.1-21.3(chr1:144927578-153223600)x3	Pathogenic

SpliceAI

101 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153031246:AGGTG:A	donor_loss	0.9800
1:153031247:GGTG:G	donor_loss	0.9800
1:153031248:G:C	donor_loss	0.9800
1:153031248:G:GG	donor_gain	0.9800
1:153032306:A:G	acceptor_gain	0.9700
1:153032322:TCCA:T	acceptor_loss	0.9600
1:153032323:CCA:C	acceptor_loss	0.9600
1:153032324:CA:C	acceptor_loss	0.9600
1:153032325:AGG:A	acceptor_loss	0.9600
1:153032326:G:A	acceptor_loss	0.9600
1:153031244:CCAG:C	donor_gain	0.9500
1:153032325:A:AG	acceptor_gain	0.9400
1:153032326:G:GG	acceptor_gain	0.9400
1:153032325:AGGAC:A	acceptor_gain	0.9300
1:153032318:T:TA	acceptor_gain	0.9200
1:153031243:ACCAG:A	donor_gain	0.9100
1:153032318:T:A	acceptor_loss	0.9100
1:153031245:CAG:C	donor_gain	0.9000
1:153032208:T:G	donor_gain	0.8900
1:153032305:A:AG	acceptor_gain	0.8900
1:153032313:T:A	acceptor_gain	0.8700
1:153032208:T:TG	donor_gain	0.8600
1:153032324:CAGGA:C	acceptor_gain	0.8600
1:153031246:AG:A	donor_gain	0.8500
1:153031247:GG:G	donor_gain	0.8500
1:153032310:ATCT:A	acceptor_gain	0.8500
1:153032300:T:TA	acceptor_gain	0.8400
1:153031709:GAAA:G	donor_gain	0.8300
1:153032325:AG:A	acceptor_gain	0.8100
1:153032326:GG:G	acceptor_gain	0.8100

AlphaMissense

577 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153032349:A:C	S2R	0.662
1:153032351:T:A	S2R	0.662
1:153032351:T:G	S2R	0.662
1:153032612:G:C	K89N	0.595
1:153032612:G:T	K89N	0.595
1:153032411:A:C	K22N	0.568
1:153032411:A:T	K22N	0.568

dbSNP variants (sampled 300 via entrez): RS1000126686 (1:153029804 C>T), RS1000251057 (1:153029759 G>A), RS1000451819 (1:153030715 C>A), RS1003674075 (1:153032953 C>T), RS1004333252 (1:153030467 A>G), RS1004612912 (1:153032725 A>G), RS1005778840 (1:153032984 G>A,C), RS1007209997 (1:153033208 C>A,T), RS1008843050 (1:153030688 A>G), RS1009196122 (1:153031220 A>G), RS1009680364 (1:153030997 A>T), RS1014289583 (1:153029790 G>A), RS1014629307 (1:153029981 C>T), RS1016080946 (1:153031700 T>C), RS1016674699 (1:153030482 T>C)

Disease associations

OMIM: gene MIM:182266 | disease phenotypes: MIM:612475

GenCC curated gene-disease

Mondo (1): chromosome 1q21.1 duplication syndrome (MONDO:0012915)

Orphanet (1): 1q21.1 microduplication syndrome (Orphanet:250994)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002740_17	Inflammatory skin disease	2.000000e-15
GCST007564_25	Asthma or allergic disease (pleiotropy)	5.000000e-09
GCST008916_87	Asthma	2.000000e-13

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567290	Chromosome 1q21.1 Duplication Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	5
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
Benzo(a)pyrene	decreases reaction, affects cotreatment, increases expression, increases methylation	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	2
Tretinoin	decreases expression	2
Valproic Acid	affects cotreatment, decreases expression, decreases methylation	2
4-oxoretinoic acid	decreases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	affects cotreatment, increases expression, decreases reaction	1
sulindac sulfide	increases expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	decreases expression, affects cotreatment	1
Alitretinoin	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Allergens	increases expression	1
Antimony Potassium Tartrate	decreases expression	1
Arsenic	decreases expression	1
Cannabidiol	increases expression	1
Catechin	affects cotreatment, decreases reaction, increases expression	1
Diuron	increases expression	1
Estradiol	decreases expression, increases expression, affects cotreatment	1
Fluorouracil	affects expression	1
Furaldehyde	decreases expression, affects cotreatment, affects localization	1
Hydralazine	affects cotreatment, decreases expression	1
Lasalocid	increases expression	1
Nickel	increases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Smoke	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight