BOLA2

Summary

BOLA2 (bolA family member 2, HGNC:29488) is a protein-coding gene on chromosome 16p11.2, encoding BolA-like protein 2 (Q9H3K6). Acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins.

This gene is located within a region of a segmental duplication on chromosome 16 and is identical to BOLA2B (bolA family member 2B). The product of this gene belongs to a family of proteins that are widely conserved and may be involved in iron maturation. Related pseudogenes are found multiple different chromosomes. Alternative splicing results in multiple transcript variants. Transcripts initiating at this locus may extend into downstream SMG1 pseudogene 6 (SMG1P6) and encode fusion proteins with a C-terminus related to SMG1 phosphatidylinositol 3-kinase-related kinase. A readthrough locus is represented with GeneID:107282092.

Source: NCBI Gene 552900 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 5 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001031827

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29488
Approved symbol	BOLA2
Name	bolA family member 2
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	My016, BOLA2A
Ensembl gene	ENSG00000183336
Ensembl biotype	protein_coding
OMIM	613182
Entrez	552900

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000330978, ENST00000692192, ENST00000856522, ENST00000925511, ENST00000925512

RefSeq mRNA: 3 — MANE Select: NM_001031827 NM_001031827, NM_001320579, NM_001421680

CCDS: CCDS32426

Canonical transcript exons

ENST00000330978 — 3 exons

Exon	Start	End
ENSE00001806596	29453593	29453732
ENSE00003592372	29454016	29454113
ENSE00003718126	29454191	29454351

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 87.27.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.08	gold quality
monocyte	CL:0000576	74.09	gold quality
prefrontal cortex	UBERON:0000451	74.07	gold quality
mucosa of transverse colon	UBERON:0004991	74.01	gold quality
leukocyte	CL:0000738	73.76	gold quality
ganglionic eminence	UBERON:0004023	73.60	gold quality
cortical plate	UBERON:0005343	73.45	gold quality
superior frontal gyrus	UBERON:0002661	72.84	gold quality
stromal cell of endometrium	CL:0002255	72.76	gold quality
primary visual cortex	UBERON:0002436	72.31	gold quality
ventricular zone	UBERON:0003053	71.32	gold quality
granulocyte	CL:0000094	71.25	gold quality
cortex of kidney	UBERON:0001225	70.69	gold quality
duodenum	UBERON:0002114	69.74	gold quality
bone marrow cell	CL:0002092	69.14	silver quality
bone marrow	UBERON:0002371	68.39	gold quality
frontal cortex	UBERON:0001870	67.95	gold quality
blood	UBERON:0000178	67.80	gold quality
right adrenal gland cortex	UBERON:0035827	67.66	gold quality
placenta	UBERON:0001987	67.50	gold quality
anterior cingulate cortex	UBERON:0009835	66.51	gold quality
right adrenal gland	UBERON:0001233	66.44	gold quality
testis	UBERON:0000473	66.38	gold quality
cerebral cortex	UBERON:0000956	66.36	gold quality
left coronary artery	UBERON:0001626	66.32	gold quality
substantia nigra	UBERON:0002038	66.23	gold quality
left testis	UBERON:0004533	66.07	gold quality
hindlimb stylopod muscle	UBERON:0004252	66.04	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	65.84	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-9	yes	17.71
E-HCAD-8	no	47.56
E-ANND-3	no	0.84

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• This study reported that all three human BolA proteins (hBolA1, hBolA2, and hBolA3) are novel non-classical secreted proteins identified with bioinformatics and molecular biology experiments. (PMID:18548201)
• apo GRX3 and apo BOLA2 form a heterotrimeric complex, composed by two BOLA2 molecules and one GRX3 molecule (PMID:26613676)
• BOLA2 shows Homo sapiens-specific duplication; this occurred around 280,000 years ago, with the duplication nearly fixed early in the human lineage (PMID:27487209)
• The Glrx3 and BolA2 bound and facilitated Fe-S incorporation into Ciapin1, a [2Fe-2S] protein functioning early in the cytosolic Fe-S assembly pathway. Thus, Glrx3.BolA is a [2Fe-2S] chaperone complex capable of transferring [2Fe-2S] clusters to apoproteins in human cells. (PMID:27519415)
• BOLA2 participates in iron homeostasis in vivo. (PMID:31668704)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	BOLA2B	ENSDARG00000111714
mus_musculus	Bola2	ENSMUSG00000047721
rattus_norvegicus	Bola2-ps1	ENSRNOG00000015333
rattus_norvegicus	AABR07034928.1	ENSRNOG00000034215
rattus_norvegicus	Bola2	ENSRNOG00000047988
drosophila_melanogaster	CG33672	FBGN0061360

Paralogs (3): BOLA3 (ENSG00000163170), BOLA2B (ENSG00000169627), BOLA1 (ENSG00000178096)

Protein

Protein identifiers

BolA-like protein 2 — Q9H3K6 (reviewed: Q9H3K6)

All UniProt accessions (2): Q9H3K6, H3BPT9

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins. Acts together with the monothiol glutaredoxin GLRX3.

Subunit / interactions. Interacts with GLRX3; forms a heterotrimeric complex composed by two BOLA2 molecules and one GLRX3 molecule; linked by [2Fe-2S] clusters.

Subcellular location. Cytoplasm. Nucleus.

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 BolA/IbaG family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H3K6-1	1	yes
Q9H3K6-2	2

RefSeq proteins (3): NP_001026997, NP_001307508, NP_001408609 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002634	BolA	Family
IPR036065	BolA-like_sf	Homologous_superfamily
IPR045115	BOL2	Family

Pfam: PF01722

UniProt features (4 total): splice variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3K6-F1	92.72	0.83

Functional residue map

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

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-447115	Interleukin-12 family signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-9020591	Interleukin-12 signaling

MSigDB gene sets: 110 (showing top): YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TTTGTAG_MIR520D, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, PUJANA_CHEK2_PCC_NETWORK, GOBP_PROTEIN_MATURATION, ONKEN_UVEAL_MELANOMA_UP, GOBP_CELL_REDOX_HOMEOSTASIS, chr16p11, GTGTTGA_MIR505, ATTACAT_MIR3803P, LIAO_METASTASIS

GO Biological Process (5): intracellular iron ion homeostasis (GO:0006879), iron-sulfur cluster assembly (GO:0016226), [2Fe-2S] cluster assembly (GO:0044571), cell redox homeostasis (GO:0045454), protein maturation (GO:0051604)

GO Molecular Function (3): iron-sulfur cluster binding (GO:0051536), 2 iron, 2 sulfur cluster binding (GO:0051537), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), iron-sulfur cluster assembly complex (GO:1990229)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Interleukin-12 signaling	1
Immune System	1
Signaling by Interleukins	1
Cytokine Signaling in Immune system	1
Interleukin-12 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytoplasm	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
metallo-sulfur cluster assembly	1
iron-sulfur cluster assembly	1
cellular homeostasis	1
gene expression	1
protein metabolic process	1
metal cluster binding	1
iron-sulfur cluster binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1132 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BOLA2	BOLA3	Q53S33	986
BOLA2	GLRX3	O76003	943
BOLA2	GLRX5	Q86SX6	746
BOLA2	CIAPIN1	Q6FI81	717
BOLA2	NFU1	Q9UMS0	577
BOLA2	LIAS	O43766	543
BOLA2	NDOR1	Q9UHB4	543
BOLA2	GPHRA	B7ZAQ6	528
BOLA2	MMS19	Q96T76	518
BOLA2	BOLA1	Q9Y3E2	517
BOLA2	SRGAP2C	P0DJJ0	502
BOLA2	ISCA2	Q86U28	497
BOLA2	GLRX	P35754	496
BOLA2	ISCU	Q9H1K1	496
BOLA2	ARHGAP11B	Q3KRB8	479

IntAct

90 interactions, top by confidence:

A	B	Type	Score
CIAPIN1	GLRX3	psi-mi:“MI:0914”(association)	0.960
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GLRX3	KLRG2	psi-mi:“MI:0914”(association)	0.640
KLRG2	GLRX3	psi-mi:“MI:0914”(association)	0.640
GLRX3	BOLA2	psi-mi:“MI:0915”(physical association)	0.560
BOLA2	GLRX3	psi-mi:“MI:0915”(physical association)	0.560
KLRG2	GXYLT2	psi-mi:“MI:0914”(association)	0.530
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
CIAPIN1	BOLA2	psi-mi:“MI:0915”(physical association)	0.500
NDOR1	BOLA2	psi-mi:“MI:0915”(physical association)	0.400
BOLA2	NARF	psi-mi:“MI:0915”(physical association)	0.400
BOLA2	SNCA	psi-mi:“MI:0915”(physical association)	0.400
MAPK6		psi-mi:“MI:0914”(association)	0.350
ARRB2		psi-mi:“MI:0914”(association)	0.350
CDK1	RBMXL2	psi-mi:“MI:0914”(association)	0.350
COQ2	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
COX15	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
DLST		psi-mi:“MI:0914”(association)	0.350
PARK7	SAP18	psi-mi:“MI:0914”(association)	0.350
SOAT1	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
VDAC1	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
DLD	EIF3D	psi-mi:“MI:0914”(association)	0.350

BioGRID (192): BOLA2 (Affinity Capture-MS), BOLA2 (Affinity Capture-MS), BOLA2 (Affinity Capture-MS), BOLA2 (Affinity Capture-MS), BOLA2B (Affinity Capture-MS), BOLA2 (Affinity Capture-MS), BOLA2B (Affinity Capture-MS), BOLA2 (Affinity Capture-MS), BOLA2B (Affinity Capture-MS), BOLA2 (Affinity Capture-MS), BOLA2B (Affinity Capture-MS), BOLA2 (Affinity Capture-MS), BOLA2B (Affinity Capture-MS), BOLA2 (Affinity Capture-MS), BOLA2B (Affinity Capture-MS)

ESM2 similar proteins: A1A4Q2, A1YER2, A1YFX9, A2T7G9, A6QP05, B0BN93, B0BNF8, B2GV38, O35331, O80526, O95154, O95671, P10950, P11172, P11441, P13439, P21126, P46597, P50053, P84169, Q0VCN1, Q28DS0, Q2HJF1, Q2QNG7, Q2QZ86, Q3T138, Q3TY86, Q5E964, Q5I0K3, Q5R4T1, Q5R514, Q5R8R4, Q5RB44, Q6P637, Q8BGS2, Q8CG45, Q8CG76, Q8CI33, Q8HZJ0, Q8JGT5

Diamond homologs: O14280, P39724, P53082, P91375, Q3SZ84, Q53S33, Q84W65, Q86HT3, Q8BGS2, Q8CEI1, Q9FIC3, Q9H3K6, Q9KPS0, Q9USK1, P0ABE2, P0ABE3, P0ABE4, P43780, P57545, Q12238, Q3E793, Q3T138, Q56585, Q5RCE5, Q682I1, Q86KD0, Q89AA2, Q9D8S9, Q9Y3E2, P29943, P73055, P0A9W6, P0A9W7, P0A9W8, Q9LF68, P45026, Q8K992, A0A1S4BZI5, A0A1S4CB73, A0A2K8FTP3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BOLA2	“form complex”	“BOLA2-GLRX3 iron-sulfur cluster assembly complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 92 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by high-kinase activity BRAF mutants	5	22.3×	2e-04
Signaling by FGFR1 in disease	5	20.6×	2e-04
MAP2K and MAPK activation	5	20.1×	2e-04
Signaling by moderate kinase activity BRAF mutants	5	17.9×	3e-04
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	17.9×	3e-04
Signaling downstream of RAS mutants	5	17.9×	3e-04
Signaling by BRAF and RAF1 fusions	6	14.4×	2e-04
Regulation of RAS by GAPs	5	13.6×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

522 predictions. Top by Δscore:

Variant	Effect	Δscore
16:29454010:CCTTA:C	donor_loss	1.0000
16:29454011:CTTAC:C	donor_loss	1.0000
16:29454012:TTACC:T	donor_loss	1.0000
16:29454013:TACCT:T	donor_loss	1.0000
16:29454014:ACCTG:A	donor_loss	1.0000
16:29454015:C:G	donor_loss	1.0000
16:29454183:CAACT:C	donor_loss	1.0000
16:29454184:AACTC:A	donor_loss	1.0000
16:29454185:ACT:A	donor_loss	1.0000
16:29454186:CTC:C	donor_loss	1.0000
16:29454187:TCA:T	donor_loss	1.0000
16:29454188:CAC:C	donor_loss	1.0000
16:29454189:A:AC	donor_gain	1.0000
16:29454190:C:CC	donor_gain	1.0000
16:29454190:CCA:C	donor_gain	1.0000
16:29453630:C:A	donor_gain	0.9900
16:29454182:TCAAC:T	donor_loss	0.9900
16:29454185:A:C	donor_gain	0.9900
16:29454186:CTCAC:C	donor_loss	0.9900
16:29454190:C:CA	donor_loss	0.9900
16:29453652:G:A	donor_gain	0.9800
16:29454014:A:AC	donor_gain	0.9800
16:29454014:A:C	donor_loss	0.9800
16:29454015:C:CC	donor_gain	0.9800
16:29454189:AC:A	donor_gain	0.9800
16:29454190:CC:C	donor_gain	0.9800
16:29454688:GACCC:G	donor_gain	0.9800
16:29453648:A:AC	donor_gain	0.9700
16:29453649:C:CC	donor_gain	0.9700
16:29455012:G:GT	donor_gain	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 42 via entrez): RS1002602928 (16:29455497 C>T), RS1233518527 (16:29455396 A>G,T), RS1344199331 (16:29455475 G>A), RS1422279401 (16:29455683 C>T), RS145372287 (16:29456331 G>A), RS1477888959 (16:29455655 C>T), RS1479644293 (16:29455272 C>T), RS1555480231 (16:29453672 G>A), RS1555480233 (16:29453921 C>G), RS1555480245 (16:29455550 T>A), RS1567288225 (16:29453180 CG>C), RS1567288275 (16:29456388 G>A), RS1567288280 (16:29456955 A>T), RS1596708925 (16:29453357 T>C), RS1596708959 (16:29455144 G>C)

Disease associations

OMIM: gene MIM:613182 | disease phenotypes: MIM:615401

GenCC curated gene-disease

Mondo (1): severe combined immunodeficiency due to CORO1A deficiency (MONDO:0014168)

Orphanet (1): Severe combined immunodeficiency due to CORO1A deficiency (Orphanet:228003)

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: yes

ChEMBL targets (1): CHEMBL5724752 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178999: Inhibition of BOLA2 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects methylation	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
ICG 001	increases expression	1
bisphenol S	decreases methylation	1
LDN 193189	affects cotreatment, decreases expression	1
Zoledronic Acid	increases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Thimerosal	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
beta-Naphthoflavone	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650994	Binding	Binding affinity to human BOLA2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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