FERD3L

Summary

FERD3L (Fer3 like bHLH transcription factor, HGNC:16660) is a protein-coding gene on chromosome 7p21.1, encoding Fer3-like protein (Q96RJ6). Transcription factor that binds to the E-box and functions as inhibitor of transcription.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in developmental process; negative regulation of DNA-templated transcription; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including floor plate development; regulation of dopaminergic neuron differentiation; and regulation of neurogenesis. Predicted to be located in chromatin and nucleus.

Source: NCBI Gene 222894 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 27 total — 2 pathogenic
• MANE Select transcript: NM_152898

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16660
Approved symbol	FERD3L
Name	Fer3 like bHLH transcription factor
Location	7p21.1
Locus type	gene with protein product
Status	Approved
Aliases	NATO3, N-TWIST, bHLHa31
Ensembl gene	ENSG00000146618
Ensembl biotype	protein_coding
OMIM	617578
Entrez	222894

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000275461

RefSeq mRNA: 1 — MANE Select: NM_152898 NM_152898

CCDS: CCDS5368

Canonical transcript exons

ENST00000275461 — 1 exons

Exon	Start	End
ENSE00000976605	19144782	19145421

Expression profiles

Bgee: expression breadth broad, 33 present calls, max score 52.15.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0465 / max 39.8005, expressed in 6 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82951	0.0236	3
82952	0.0136	2
82950	0.0093	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	52.15	silver quality
cortical plate	UBERON:0005343	40.82	gold quality
bone marrow cell	CL:0002092	38.37	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
prefrontal cortex	UBERON:0000451	36.83	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
placenta	UBERON:0001987	35.94	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	35.22	gold quality
substantia nigra	UBERON:0002038	34.38	gold quality
frontal cortex	UBERON:0001870	33.95	gold quality
right atrium auricular region	UBERON:0006631	33.51	silver quality
skin of leg	UBERON:0001511	33.26	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	33.22	silver quality
bone marrow	UBERON:0002371	32.87	gold quality
muscle tissue	UBERON:0002385	32.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
right uterine tube	UBERON:0001302	32.02	gold quality
tonsil	UBERON:0002372	31.89	gold quality
urinary bladder	UBERON:0001255	31.74	gold quality
right coronary artery	UBERON:0001625	31.61	silver quality
cerebral cortex	UBERON:0000956	31.60	gold quality
superior frontal gyrus	UBERON:0002661	31.31	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	31.11	silver quality
islet of Langerhans	UBERON:0000006	30.91	gold quality
Brodmann (1909) area 9	UBERON:0013540	30.83	silver quality
minor salivary gland	UBERON:0001830	30.05	silver quality
saliva-secreting gland	UBERON:0001044	29.97	silver quality
right frontal lobe	UBERON:0002810	29.95	silver quality
zone of skin	UBERON:0000014	29.88	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.17

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOXA2

JASPAR motifs

Motif	Name	Family
MA1485.1	FERD3L	Tal-related

JASPAR matrix evidence (PMIDs): PMID:17027923

Upstream regulators (CollecTRI, top): FOXA2

Literature-anchored findings (GeneRIF, showing 2)

• Identification and genomic structure of Nato3 in fly, mouse and man. Nervous system expression detected in fly and mouse. (PMID:11472856)
• the risk allele Rs10230207 for patients with intracranial aneurysm is not associated with changes in FERD3L gene expression, but is associated with increased HDAC9 and decrease in TWIST1 mRNA expression (PMID:30919159)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	ferd3l	ENSDARG00000092160
mus_musculus	Ferd3l	ENSMUSG00000046518
rattus_norvegicus	Ferd3l	ENSRNOG00000011091
drosophila_melanogaster	twi	FBGN0003900
drosophila_melanogaster	HLH54F	FBGN0022740
drosophila_melanogaster	Hand	FBGN0032209
drosophila_melanogaster	Fer3	FBGN0037937
drosophila_melanogaster	CG33557	FBGN0053557
caenorhabditis_elegans		WBGENE00001953
caenorhabditis_elegans		WBGENE00001956

Paralogs (13): HAND1 (ENSG00000113196), TCF21 (ENSG00000118526), TWIST1 (ENSG00000122691), TCF15 (ENSG00000125878), TCF23 (ENSG00000163792), HAND2 (ENSG00000164107), PTF1A (ENSG00000168267), MSC (ENSG00000178860), FIGLA (ENSG00000183733), BHLHA9 (ENSG00000205899), TWIST2 (ENSG00000233608), SCX (ENSG00000260428), TCF24 (ENSG00000261787)

Protein

Protein identifiers

Fer3-like protein — Q96RJ6 (reviewed: Q96RJ6)

Alternative names: Basic helix-loop-helix protein N-twist, Class A basic helix-loop-helix protein 31, Nephew of atonal 3, Neuronal twist

All UniProt accessions (1): Q96RJ6

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds to the E-box and functions as inhibitor of transcription. DNA binding requires dimerization with an E protein. Inhibits transcription activation by ASCL1/MASH1 by sequestering E proteins.

Subunit / interactions. Heterodimer with TCF3/E12. Interacts with the bHLH domain of TCF3/E12.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_690862* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050283	E-box_TF_Regulators	Family

Pfam: PF00010

UniProt features (6 total): chain 1, domain 1, region of interest 1, compositionally biased region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RJ6-F1	71.10	0.38

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 64 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEUROGENESIS, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, EFC_Q6, TCF4_Q5, GGARNTKYCCA_UNKNOWN, GRE_C, TGGNNNNNNKCCAR_UNKNOWN, FREAC4_01, POU3F2_02, HAND1E47_01, GOBP_EMBRYO_DEVELOPMENT

GO Biological Process (8): regulation of transcription by RNA polymerase II (GO:0006357), developmental process (GO:0032502), floor plate development (GO:0033504), negative regulation of DNA-templated transcription (GO:0045892), cell development (GO:0048468), regulation of neurogenesis (GO:0050767), regulation of dopaminergic neuron differentiation (GO:1904338), negative regulation of transcription by RNA polymerase II (GO:0000122)

GO Molecular Function (8): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), protein dimerization activity (GO:0046983), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
anatomical structure development	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
biological_process	1
neural tube development	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
cell differentiation	1
cellular developmental process	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
regulation of neuron differentiation	1
dopaminergic neuron differentiation	1
negative regulation of DNA-templated transcription	1
transcription cis-regulatory region binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

616 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FERD3L	GPR137	Q96N19	463
FERD3L	HSPA12B	Q96MM6	438
FERD3L	POLR1F	Q3B726	431
FERD3L	SSR4	P51571	427
FERD3L	LMX1A	Q8TE12	426
FERD3L	CITED4	Q96RK1	416
FERD3L	ICAM4	Q14773	412
FERD3L	SNX13	Q9Y5W8	410
FERD3L	FOXA2	Q9Y261	407
FERD3L	NDEL1	Q9GZM8	395
FERD3L	FOXA1	P55317	387
FERD3L	LMX1B	O60663	386
FERD3L	MZF1	P28698	385
FERD3L	XRCC3	O43542	379
FERD3L	HDAC9	Q9UKV0	364

IntAct

17 interactions, top by confidence:

A	B	Type	Score
TCF4	FERD3L	psi-mi:“MI:0915”(physical association)	0.740
FERD3L	TCF4	psi-mi:“MI:0915”(physical association)	0.740
FAM9B	FERD3L	psi-mi:“MI:0915”(physical association)	0.670
FERD3L	FAM9B	psi-mi:“MI:0915”(physical association)	0.670
FERD3L	MAGEB4	psi-mi:“MI:0915”(physical association)	0.560
SGTA	FERD3L	psi-mi:“MI:0915”(physical association)	0.560
MAGEB4	FERD3L	psi-mi:“MI:0915”(physical association)	0.560
FERD3L	SGTA	psi-mi:“MI:0915”(physical association)	0.560
FERD3L	USP19	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): FERD3L (Two-hybrid), FERD3L (Two-hybrid), FERD3L (Two-hybrid), FERD3L (Two-hybrid), TCF3 (Affinity Capture-MS), TCF12 (Affinity Capture-MS), TCF4 (Affinity Capture-MS), USP19 (Affinity Capture-MS), HEXIM2 (Affinity Capture-MS), NES (Affinity Capture-MS), DMWD (Affinity Capture-MS), CORO2A (Affinity Capture-MS), FERD3L (Two-hybrid), FERD3L (Two-hybrid), FERD3L (Two-hybrid)

ESM2 similar proteins: A2PZN8, A2XY47, A2Z730, A7YY73, B8APB5, B8BLA3, F4JCN9, O54791, O57337, P13027, P13097, P24068, P70120, Q00P32, Q03062, Q07291, Q0DUR2, Q0JCC3, Q0JJ01, Q0VH33, Q14582, Q17RB8, Q28DB3, Q2KIL7, Q2R1J3, Q338G6, Q39140, Q4VBF2, Q5D0W8, Q5TA89, Q5ZI27, Q60948, Q61858, Q6IVC3, Q7SX95, Q7X742, Q7X993, Q7XJU2, Q8GW32, Q8WWL2

Diamond homologs: A3KNX5, O13125, O13126, O57598, P48985, P48987, P70661, Q10574, Q4ZHW1, Q5RJB0, Q7RTS1, Q7RTU4, Q7ZSX3, Q8AW52, Q8N100, Q923Z4, Q96RJ6, Q9QX98, Q9VGJ5, A8E5T6, B6VQA1, O16867, O35437, O42202, O42606, O43680, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P13903, P17542, P22091, P24899, P26687, P46581, P57100

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	24
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2664505	GRCh37/hg19 7p21.1(chr7:19066802-19662813)x1	Pathogenic
58540	GRCh38/hg38 7p21.1(chr7:18931530-19221396)x1	Pathogenic

SpliceAI

129 predictions. Top by Δscore:

Variant	Effect	Δscore
7:19145127:T:TA	donor_gain	0.8700
7:19145029:T:TA	donor_gain	0.7800
7:19145217:C:A	donor_gain	0.7500
7:19145133:T:TA	donor_gain	0.6900
7:19144984:T:TA	donor_gain	0.6700
7:19145206:T:TA	donor_gain	0.6600
7:19145216:T:TA	donor_gain	0.6600
7:19144872:T:A	donor_gain	0.6500
7:19145130:T:TA	donor_gain	0.6400
7:19145111:T:TA	donor_gain	0.6300
7:19145190:TCAA:T	donor_gain	0.6300
7:19145070:A:AC	donor_gain	0.6200
7:19144975:TGGGC:T	donor_gain	0.5900
7:19144825:C:CT	donor_gain	0.5600
7:19144826:T:TT	donor_gain	0.5600
7:19144973:CGTGG:C	donor_gain	0.5600
7:19144974:GTGGG:G	donor_gain	0.5600
7:19144993:G:C	donor_gain	0.5500
7:19145105:G:C	donor_gain	0.5300
7:19145160:T:TA	donor_gain	0.5200
7:19145053:GGCGC:G	acceptor_gain	0.5100
7:19145160:TCGC:T	donor_gain	0.5100
7:19145121:T:A	donor_gain	0.4900
7:19145203:T:TA	donor_gain	0.4900
7:19144824:A:AC	donor_gain	0.4700
7:19145023:T:TA	donor_gain	0.4700
7:19144850:T:A	donor_gain	0.4600
7:19144884:CAG:C	donor_gain	0.4600
7:19145107:C:T	donor_gain	0.4600
7:19145030:C:A	donor_gain	0.4500

AlphaMissense

1077 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:19144935:A:G	L143P	0.999
7:19144935:A:T	L143H	0.999
7:19144992:A:G	L124P	0.999
7:19145030:C:A	R111S	0.999
7:19145030:C:G	R111S	0.999
7:19145038:G:T	R109S	0.999
7:19145056:G:T	R103S	0.999
7:19144929:A:G	L145P	0.998
7:19145000:A:C	F121L	0.998
7:19145000:A:T	F121L	0.998
7:19145002:A:G	F121L	0.998
7:19145013:A:G	L117P	0.998
7:19145033:T:A	E110D	0.998
7:19145033:T:G	E110D	0.998
7:19145034:T:A	E110V	0.998
7:19144926:G:T	A146D	0.997
7:19144932:C:G	R144P	0.997
7:19144978:G:A	P129S	0.997
7:19145001:A:C	F121C	0.997
7:19145025:C:G	R113P	0.997
7:19145031:C:A	R111M	0.997
7:19145031:C:G	R111T	0.997
7:19145034:T:G	E110A	0.997
7:19145035:C:T	E110K	0.997
7:19145037:C:G	R109P	0.997
7:19145046:G:T	A106D	0.997
7:19144927:C:G	A146P	0.996
7:19144936:G:A	L143F	0.996
7:19144948:G:C	R139G	0.996
7:19144950:G:A	S138F	0.996

dbSNP variants (sampled 300 via entrez): RS1000926523 (7:19144932 C>CGGA), RS1002546721 (7:19146562 T>A), RS1002597405 (7:19146757 C>A), RS1004948516 (7:19145616 G>C), RS1007140560 (7:19146833 A>G), RS1008387318 (7:19145827 T>A,C,G), RS1008449499 (7:19146412 G>A,C), RS1009072734 (7:19145690 G>A,T), RS1009145988 (7:19147008 C>G,T), RS1009177983 (7:19146066 G>A), RS1009538085 (7:19145831 A>T), RS1010137628 (7:19145075 C>A), RS1010783869 (7:19147203 G>A,C), RS1011949487 (7:19146510 C>T), RS1011980676 (7:19146701 G>A,C)

Disease associations

OMIM: gene MIM:617578 | disease phenotypes: MIM:101400

GenCC curated gene-disease

Mondo (1): Saethre-Chotzen syndrome (MONDO:0007042)

Orphanet (1): Saethre-Chotzen syndrome (Orphanet:794)

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001762_923	Obesity-related traits	5.000000e-06
GCST002550_8	Allergic rhinitis	2.000000e-08
GCST002875_21	Diisocyanate-induced asthma	1.000000e-06
GCST006979_329	Heel bone mineral density	4.000000e-09
GCST008839_229	Height	6.000000e-10
GCST008839_48	Height	3.000000e-15
GCST008839_599	Height	7.000000e-20
GCST009724_9	Vertical cup-disc ratio (multi-trait analysis)	2.000000e-09
GCST010002_345	Refractive error	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0009270	heel bone mineral density
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	increases methylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
Arsenic Trioxide	affects binding, decreases reaction	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Mercury	decreases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1R4	SEES3-1V human FERD3L, clone1	Embryonic stem cell	Male
CVCL_A1R5	SEES3-1V human FERD3L, clone2	Embryonic stem cell	Male
CVCL_A1R6	SEES3-1V human FERD3L, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04676399	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Improving Pain Management Via Spinal Cord Stimulation and Blood Pressure Reduction
NCT03670147	Not specified	TERMINATED	Paresthesia Free Spinal Cord Stimulation (PF-SCS)
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04548375	Not specified	RECRUITING	Multicenter Outcome Registry of AnaLgesic Effect of SCS(MORALES) Registry Protocol
NCT05466110	Not specified	UNKNOWN	Spinal Cord Stimulation Versus Instrumentation for FBSS
NCT05540756	Not specified	WITHDRAWN	Study on the Use of Intraoperative Neurophysiological Monitoring in Spinal Cord Stimulator Trials
NCT07535372	Not specified	NOT_YET_RECRUITING	ASO Treatment for Syndromic Craniosynostoses