LEFTY1

Summary

LEFTY1 (left-right determination factor 1, HGNC:6552) is a protein-coding gene on chromosome 1q42.12, encoding Left-right determination factor 1 (O75610). Required for left-right axis determination as a regulator of LEFTY2 and NODAL.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which plays a role in left-right asymmetry determination of organ systems during development. This gene is closely linked to both a related family member and a related pseudogene.

Source: NCBI Gene 10637 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 84 total
• MANE Select transcript: NM_020997

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6552
Approved symbol	LEFTY1
Name	left-right determination factor 1
Location	1q42.12
Locus type	gene with protein product
Status	Approved
Aliases	LEFTYB
Ensembl gene	ENSG00000243709
Ensembl biotype	protein_coding
OMIM	603037
Entrez	10637

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000272134, ENST00000492457, ENST00000911495, ENST00000946628

RefSeq mRNA: 1 — MANE Select: NM_020997 NM_020997

CCDS: CCDS1548

Canonical transcript exons

ENST00000272134 — 4 exons

Exon	Start	End
ENSE00000961957	225886282	225887090
ENSE00002238957	225888817	225889146
ENSE00003506858	225887399	225887638
ENSE00003584744	225887786	225888032

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 95.85.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9312 / max 176.5783, expressed in 94 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17732	1.9312	94

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	95.85	gold quality
body of pancreas	UBERON:0001150	91.22	gold quality
rectum	UBERON:0001052	90.44	gold quality
transverse colon	UBERON:0001157	87.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.71	silver quality
pancreas	UBERON:0001264	78.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.86	gold quality
colon	UBERON:0001155	74.67	gold quality
endometrium	UBERON:0001295	74.64	gold quality
vermiform appendix	UBERON:0001154	72.14	gold quality
colonic epithelium	UBERON:0000397	69.69	gold quality
monocyte	CL:0000576	69.66	gold quality
intestine	UBERON:0000160	69.38	gold quality
leukocyte	CL:0000738	69.05	gold quality
cerebellar hemisphere	UBERON:0002245	66.46	gold quality
cerebellar cortex	UBERON:0002129	66.40	gold quality
cerebellum	UBERON:0002037	66.29	gold quality
right hemisphere of cerebellum	UBERON:0014890	66.25	gold quality
right frontal lobe	UBERON:0002810	65.28	gold quality
nucleus accumbens	UBERON:0001882	65.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	64.17	gold quality
frontal cortex	UBERON:0001870	63.74	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	63.73	gold quality
prefrontal cortex	UBERON:0000451	63.04	gold quality
cerebral cortex	UBERON:0000956	62.95	gold quality
anterior cingulate cortex	UBERON:0009835	62.66	gold quality
putamen	UBERON:0001874	62.58	gold quality
primary visual cortex	UBERON:0002436	62.31	gold quality
caudate nucleus	UBERON:0001873	62.21	gold quality
brain	UBERON:0000955	61.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	454.45
E-MTAB-3929	yes	215.24
E-ANND-3	yes	8.29
E-MTAB-8060	no	107.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF4, OTX2, POU5F1, SOX2, TCF12, TCF3, ZNF296

miRNA regulators (miRDB)

39 targeting LEFTY1, 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-8485	100.00	77.57	4731
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4324	99.04	70.14	1569

Literature-anchored findings (GeneRIF, showing 15)

• nodal and the inhibitors of Nodal signaling, lefty-A and lefty-B, are down-regulated very early upon differentiation of human embryonic stem cells (PMID:15308665)
• LEFTY proteins, which are known to play a major role during mouse gastrulation, are transiently expressed during human embryonic stem cell differentiation. (PMID:17038673)
• The expression of Nodal in normal and malignant endometrial cells that lack Lefty strongly supports an important role for this embryonic morphogen in the tissue remodelling events that occur across the menstrual cycle and in tumourogenesis. (PMID:19874624)
• Findings suggest that Lefty1 is negatively modulated by miR-302s in hESCs, which plays an important role in maintaining the balance between pluripotency and germ layer specification. (PMID:21266536)
• Findings show that during embryonic development, EBAF/LEFTY B plays important roles in decidualization and embryo implantation. (PMID:21401636)
• Data suggest that Lefty is a novel TGF-beta target molecule that mediates growth inhibition of pancreatic cancer cells. (PMID:22441145)
• Reprogrammed cancer cells share the mechanism for expression of Lefty with induced pluripotent cancer cells (iPS), thus contributing to the cancerous transformation of iPS cells. (PMID:23407711)
• The mRNA levels of LSD1 and beta-catenin are inversely correlated with the levels of Lefty1 in pancreas and breast tumors. (PMID:23592333)
• Lefty1 could regulates the cell cycle via modulating the expressions of P57 and cyclin D1 and then inhibit the decidualization in vitro. (PMID:25339094)
• functional role of LEFTY during progesterone therapy for endometrial carcinoma (PMID:29268772)
• Studied genes involved in TGF-beta/BMP signaling pathway including chorionic villi LEFTY1 expression levels in association with miscarriage. (PMID:30027725)
• Expression of Lefty predicts Merkel cell carcinoma-specific death. (PMID:32022949)
• Requirements of LEFTY and Nodal overexpression for tumor cell survival under hypoxia in glioblastoma. (PMID:33111989)
• Expression of Cytokine-Coding Genes BMP8B, LEFTY1 and INSL5 Could Distinguish between Ulcerative Colitis and Crohn’s Disease. (PMID:34680872)
• Association of maternal hypertension and diabetes with variants of the NKX2-5, LEFTY1 and LEFTY2 genes in children with congenital heart defects: a case-control study from Pakistani Population. (PMID:37097539)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	lft1	ENSDARG00000019920
danio_rerio	lft2	ENSDARG00000044059
mus_musculus	Lefty1	ENSMUSG00000038793
mus_musculus	Lefty2	ENSMUSG00000066652
rattus_norvegicus	Lefty1	ENSRNOG00000003263
rattus_norvegicus	Lefty2	ENSRNOG00000060325

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), TGFB1 (ENSG00000105329), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF5 (ENSG00000125965), GDF1 (ENSG00000130283), BMP15 (ENSG00000130385), GDF15 (ENSG00000130513), GDF11 (ENSG00000135414), MSTN (ENSG00000138379), INHBE (ENSG00000139269), LEFTY2 (ENSG00000143768), GDF7 (ENSG00000143869), BMP3 (ENSG00000152785), BMP6 (ENSG00000153162), GDF6 (ENSG00000156466), NODAL (ENSG00000156574), INHBB (ENSG00000163083), BMP10 (ENSG00000163217), GDF9 (ENSG00000164404), INHBC (ENSG00000175189), BMP8A (ENSG00000183682), GDF3 (ENSG00000184344), GDF2 (ENSG00000263761), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Left-right determination factor 1 — O75610 (reviewed: O75610)

Alternative names: Left-right determination factor B, Protein lefty-1, Protein lefty-B

All UniProt accessions (1): O75610

UniProt curated annotations — full annotation on UniProt →

Function. Required for left-right axis determination as a regulator of LEFTY2 and NODAL.

Subcellular location. Secreted.

Post-translational modifications. The processing of the protein may also occur at the second R-X-X-R site located at AA 132-135. Processing appears to be regulated in a cell-type specific manner.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (1): NP_066277* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001111	TGF-b_propeptide	Domain
IPR001839	TGF-b_C	Domain
IPR003942	LRDF	Family
IPR015615	TGF-beta-like	Family
IPR017948	TGFb_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019, PF00688

UniProt features (12 total): sequence variant 4, disulfide bond 4, signal peptide 1, propeptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75610-F1	78.45	0.27

Functional residue map

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

Disulfide bonds (4): 251–264, 263–316, 293–351, 297–353

Glycosylation sites (1): 158

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-1433617	Regulation of signaling by NODAL
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 125 (showing top): GOBP_AXIS_SPECIFICATION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, MODULE_379, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, GOBP_HEART_MORPHOGENESIS, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_UP, GOBP_RESPONSE_TO_BMP, MODULE_88, GOBP_RESPONSE_TO_GROWTH_FACTOR, GOMF_CYTOKINE_ACTIVITY, GOBP_ANTERIOR_POSTERIOR_AXIS_SPECIFICATION

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), heart morphogenesis (GO:0003007), transforming growth factor beta receptor signaling pathway (GO:0007179), determination of left/right symmetry (GO:0007368), anterior/posterior axis specification (GO:0009948), BMP signaling pathway (GO:0030509)

GO Molecular Function (3): cytokine activity (GO:0005125), transforming growth factor beta receptor binding (GO:0005160), growth factor activity (GO:0008083)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Developmental Biology	1
Signaling by NODAL	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transforming growth factor beta receptor superfamily signaling pathway	2
receptor ligand activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
heart development	1
animal organ morphogenesis	1
cellular response to transforming growth factor beta stimulus	1
determination of bilateral symmetry	1
left/right pattern formation	1
axis specification	1
anterior/posterior pattern specification	1
cellular response to BMP stimulus	1
cytokine receptor binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LEFTY1	NODAL	Q96S42	877
LEFTY1	PITX2	Q99697	868
LEFTY1	ACVR2B	Q13705	833
LEFTY1	ZIC3	O60481	798
LEFTY1	CRIPTO	P13385	786
LEFTY1	CFC1	P0CG37	741
LEFTY1	CER1	O95813	690
LEFTY1	FGF8	P55075	630
LEFTY1	GDF3	Q9NR23	628
LEFTY1	NANOG	Q9H9S0	623
LEFTY1	GDF1	P27539	623
LEFTY1	GATA4	P43694	615
LEFTY1	POU5F1	P31359	589
LEFTY1	SOX2	P48431	588
LEFTY1	ZFP42	Q96MM3	582

IntAct

3 interactions, top by confidence:

A	B	Type	Score
LEFTY1	LEFTY2	psi-mi:“MI:0914”(association)	0.530

BioGRID (5): LEFTY2 (Affinity Capture-MS), MTOR (Affinity Capture-MS), LEFTY1 (Affinity Capture-RNA), MTOR (Affinity Capture-MS), LEFTY2 (Affinity Capture-MS)

ESM2 similar proteins: D3YZZ2, E7ERA6, F2Z333, H3BV60, O00292, O18796, O43508, O43612, O54907, O55232, O55241, O60391, O75462, O75610, O77668, O95633, O95685, P13224, P41155, P56717, Q02833, Q06643, Q14626, Q1LZB9, Q2TBM7, Q4V892, Q5RF19, Q5TM22, Q6IA17, Q6UXT9, Q6ZMM2, Q862Z7, Q86VR8, Q86YD3, Q8BQB4, Q8NBV8, Q8TAD2, Q99640, Q99MF4, Q9BZR6

Diamond homologs: O00292, O75610, P57785, Q64280, Q66KL4, P25703

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POU5F1	“up-regulates quantity by expression”	LEFTY1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1119 predictions. Top by Δscore:

Variant	Effect	Δscore
1:225887086:GAGCT:G	acceptor_gain	1.0000
1:225887089:CT:C	acceptor_gain	1.0000
1:225887091:C:CC	acceptor_gain	1.0000
1:225887520:C:CA	donor_gain	1.0000
1:225887634:CCAGC:C	acceptor_gain	1.0000
1:225887635:CAGCC:C	acceptor_gain	1.0000
1:225888028:CACCT:C	acceptor_gain	1.0000
1:225888029:ACCT:A	acceptor_gain	1.0000
1:225888030:CCTC:C	acceptor_gain	1.0000
1:225888031:CT:C	acceptor_gain	1.0000
1:225888033:C:CA	acceptor_loss	1.0000
1:225888033:C:CC	acceptor_gain	1.0000
1:225888034:T:G	acceptor_loss	1.0000
1:225888814:CA:C	donor_loss	1.0000
1:225887087:AGCT:A	acceptor_gain	0.9900
1:225887088:GCT:G	acceptor_gain	0.9900
1:225887088:GCTC:G	acceptor_loss	0.9900
1:225887088:GCTCT:G	acceptor_gain	0.9900
1:225887089:CTC:C	acceptor_gain	0.9900
1:225887089:CTCTG:C	acceptor_gain	0.9900
1:225887090:TC:T	acceptor_loss	0.9900
1:225887090:TCT:T	acceptor_gain	0.9900
1:225887090:TCTGT:T	acceptor_gain	0.9900
1:225887091:C:A	acceptor_loss	0.9900
1:225887091:C:CA	acceptor_loss	0.9900
1:225887091:C:G	acceptor_gain	0.9900
1:225887092:T:A	acceptor_loss	0.9900
1:225887093:G:C	acceptor_gain	0.9900
1:225887395:CTACC:C	donor_loss	0.9900
1:225887396:TA:T	donor_loss	0.9900

AlphaMissense

2350 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:225886881:C:G	C316S	0.990
1:225886882:A:T	C316S	0.990
1:225887611:C:A	W175C	0.990
1:225887611:C:G	W175C	0.990
1:225886950:C:G	C293S	0.986
1:225886951:A:T	C293S	0.986
1:225887474:A:C	F221C	0.986
1:225886882:A:G	C316R	0.984
1:225886776:C:G	C351S	0.983
1:225886777:A:T	C351S	0.983
1:225886997:C:A	W277C	0.983
1:225886997:C:G	W277C	0.983
1:225887575:C:A	W187C	0.982
1:225887575:C:G	W187C	0.982
1:225886951:A:G	C293R	0.981
1:225887843:A:T	V147D	0.981
1:225887790:A:G	S165P	0.979
1:225886770:C:G	C353S	0.978
1:225886771:A:T	C353S	0.978
1:225886985:C:A	W281C	0.976
1:225886985:C:G	W281C	0.976
1:225887040:C:G	C263S	0.974
1:225887041:A:G	C263R	0.974
1:225887041:A:T	C263S	0.974
1:225887473:A:C	F221L	0.974
1:225887473:A:T	F221L	0.974
1:225887475:A:G	F221L	0.974
1:225886880:G:C	C316W	0.973
1:225887981:A:C	F101C	0.973
1:225886777:A:G	C351R	0.972

dbSNP variants (sampled 300 via entrez): RS1001093835 (1:225885958 G>A), RS1001445240 (1:225886159 C>G), RS1001832197 (1:225886620 A>G), RS1003215549 (1:225888047 A>C,G), RS1004684843 (1:225891121 C>G), RS1004778781 (1:225885846 CGAG>C), RS1005405089 (1:225887793 C>A,G), RS1005463097 (1:225888392 T>C), RS1005561477 (1:225889424 G>C,T), RS1005952165 (1:225890443 G>T), RS1006895577 (1:225886006 A>C), RS1007180002 (1:225886203 C>T), RS1007295494 (1:225887085 T>C), RS1007504182 (1:225890039 C>T), RS1007758398 (1:225887300 C>T)

Disease associations

OMIM: gene MIM:603037 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	2
Estradiol	decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
Aflatoxin B1	increases expression	2
fluorene-9-bisphenol	increases expression	1
propionaldehyde	decreases expression	1
bisphenol A	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
bisphenol S	increases expression	1
Decitabine	affects expression	1
Fulvestrant	decreases reaction, increases expression	1
Ethanol	increases expression	1
Aldehydes	decreases expression	1
Cisplatin	affects expression	1
Dexamethasone	increases expression, decreases reaction	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Progesterone	increases expression, affects cotreatment	1
Rifampin	affects cotreatment, increases expression	1
Rotenone	increases expression	1
Teratogens	increases expression	1
Triclosan	increases expression, affects cotreatment	1
Mifepristone	decreases reaction, increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Genistein	increases expression, decreases reaction	1

Clinical trials (associated diseases)

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