IBA57

Summary

IBA57 (iron-sulfur cluster assembly factor IBA57, HGNC:27302) is a protein-coding gene on chromosome 1q42.13, encoding Iron-sulfur cluster assembly factor IBA57, mitochondrial (Q5T440). Mitochondrial protein involved in the maturation of mitochondrial [4Fe-4S]-proteins in the late stage of the iron-sulfur cluster assembly pathway. It is a selective cancer dependency (DepMap: 18.6% of cell lines).

The protein encoded by this gene localizes to the mitochondrion and is part of the iron-sulfur cluster assembly pathway. The encoded protein functions late in the biosynthesis of mitochondrial 4Fe-4S proteins. Defects in this gene have been associated with autosomal recessive spastic paraplegia-74 and with multiple mitochondrial dysfunctions syndrome-3. Two transcript variants encoding different isoforms have been found for this gene. The smaller isoform is not likely to be localized to the mitochondrion since it lacks the amino-terminal transit peptide.

Source: NCBI Gene 200205 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 342 total — 22 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 62
• Cancer dependency (DepMap): dependent in 18.6% of screened cell lines
• MANE Select transcript: NM_001010867

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27302
Approved symbol	IBA57
Name	iron-sulfur cluster assembly factor IBA57
Location	1q42.13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12734
Ensembl gene	ENSG00000181873
Ensembl biotype	protein_coding
OMIM	615316
Entrez	200205

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000366711, ENST00000484749, ENST00000546123, ENST00000949083

RefSeq mRNA: 2 — MANE Select: NM_001010867 NM_001010867, NM_001310327

CCDS: CCDS31046

Canonical transcript exons

ENST00000366711 — 3 exons

Exon	Start	End
ENSE00001295878	228165804	228166157
ENSE00003665231	228175122	228182257
ENSE00003684375	228174692	228175029

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 90.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.8981 / max 164.3036, expressed in 1783 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8932	8.6829	1780
8933	0.2152	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	90.20	silver quality
superficial temporal artery	UBERON:0001614	82.03	silver quality
gastrocnemius	UBERON:0001388	81.76	gold quality
sperm	CL:0000019	81.24	silver quality
muscle of leg	UBERON:0001383	81.04	gold quality
buccal mucosa cell	CL:0002336	80.95	gold quality
mucosa of paranasal sinus	UBERON:0005030	79.50	silver quality
left testis	UBERON:0004533	78.04	gold quality
right testis	UBERON:0004534	77.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.38	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	77.22	gold quality
heart left ventricle	UBERON:0002084	76.88	gold quality
cardiac ventricle	UBERON:0002082	76.55	gold quality
testis	UBERON:0000473	76.12	gold quality
apex of heart	UBERON:0002098	75.94	gold quality
mucosa of transverse colon	UBERON:0004991	75.84	gold quality
vastus lateralis	UBERON:0001379	75.57	silver quality
right adrenal gland	UBERON:0001233	75.41	gold quality
endothelial cell	CL:0000115	75.37	gold quality
epithelium of nasopharynx	UBERON:0001951	75.23	silver quality
quadriceps femoris	UBERON:0001377	75.15	silver quality
esophagus squamous epithelium	UBERON:0006920	75.03	gold quality
right adrenal gland cortex	UBERON:0035827	75.00	gold quality
right lobe of liver	UBERON:0001114	74.96	gold quality
left adrenal gland	UBERON:0001234	74.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.18	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.01	gold quality
skeletal muscle tissue	UBERON:0001134	73.69	gold quality
tibialis anterior	UBERON:0001385	73.68	silver quality
bone marrow	UBERON:0002371	73.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

199 targeting IBA57, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-141-3P	99.94	72.79	2421

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 18.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• Required for functional heme biosynthesis in erythroid cells. (PMID:19656490)
• ISCA1, ISCA2, and IBA57 were depleted by RNA interference. Depleted cells contained massively swollen and enlarged mitochondria that were virtually devoid of cristae membranes, demonstrating the importance of these proteins for mitochondrial biogenesis. (PMID:22323289)
• Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. (PMID:23462291)
• Findings reinforce the suggested specific function of IBA57 in mitochondrial [4Fe-4S] protein maturation and provide additional evidence for its role in hereditary spastic paraplegia (PMID:25609768)
• Description of four unrelated patients carrying novel mutations in IBA57; study expands the array of the genotypic variation of IBA57 and delineates the leukodystrophic pattern of IBA57 deficient patients (PMID:27785568)
• Combined with previously reported patient studies, our findings suggest that defects in IBA57 can produce diverse phenotypes. IBA57 should be considered a candidate gene for cavitating leukoencephalopathy (PMID:28671726)
• a patient with infantile-onset optic atrophy and asymptomatic white matter involvement, thus broadening the phenotypic spectrum of biallelic IBA57 mutations. (PMID:30258207)
• Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of the mitochondrial iron-sulfur cluster assembly machinery. (PMID:31831856)
• Defects in the Maturation of Mitochondrial Iron-Sulfur Proteins: Biophysical Investigation of the MMDS3 Causing Gly104Cys Variant of IBA57. (PMID:39408793)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	iba57	ENSDARG00000063446
mus_musculus	Iba57	ENSMUSG00000049287
rattus_norvegicus	Iba57	ENSRNOG00000068756
drosophila_melanogaster	CG8043	FBGN0037610
caenorhabditis_elegans	F39H2.3	WBGENE00009563

Protein

Protein identifiers

Iron-sulfur cluster assembly factor IBA57, mitochondrial — Q5T440 (reviewed: Q5T440)

Alternative names: Iron-sulfur cluster assembly factor homolog

All UniProt accessions (1): Q5T440

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial protein involved in the maturation of mitochondrial [4Fe-4S]-proteins in the late stage of the iron-sulfur cluster assembly pathway. Operates in cooperation with ISCA2 in the maturation of [4Fe-4S] proteins. Involved in the maturation of mitochondrial 2Fe-2S proteins in the late stage of the iron-sulfur cluster assembly pathway.

Subunit / interactions. Monomer. Heterotetramer; forms a dimer of dimers with ISCA2. Interacts with [2Fe-2S]-ISCA2 forming the heterodimer [2Fe- 2S]-ISCA2-IBA57 complex; [2Fe-2S] cluster binding is absolutely required to promote the complex formation.

Subcellular location. Mitochondrion.

Tissue specificity. Expressed in skin fibroblasts and skeletal muscle (at protein level).

Disease relevance. Multiple mitochondrial dysfunctions syndrome 3 (MMDS3) [MIM:615330] A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death. Some patients show failure to thrive, pulmonary hypertension, hypotonia and irritability. Biochemical features include severe combined deficiency of the 2-oxoacid dehydrogenases, defective lipoic acid synthesis and reduction in activity of mitochondrial respiratory chain complexes. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 74, autosomal recessive (SPG74) [MIM:616451] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG74 is characterized by a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy with childhood-onset and slow progression into late adulthood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the GcvT family. CAF17/IBA57 subfamily.

RefSeq proteins (2): NP_001010867, NP_001297256 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017703	YgfZ/CAF17_C	Domain
IPR027266	TrmE/GcvT-like	Homologous_superfamily
IPR045179	YgfZ/GcvT	Family
IPR057460	CAF17_C	Domain

Pfam: PF25455

UniProt features (40 total): strand 19, helix 10, turn 3, modified residue 2, sequence variant 2, mutagenesis site 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6GEU	X-RAY DIFFRACTION	1.55
6QE3	X-RAY DIFFRACTION	1.75
6QE4	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T440-F1	86.07	0.73

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 (2): 309, 309

Mutagenesis-validated functional residues (2):

Position	Phenotype
146	abolishes interaction with isca2.
259	abolishes the formation of the [2fe-2s] isca2-iba57 complex formation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (2): heme biosynthetic process (GO:0006783), iron-sulfur cluster assembly (GO:0016226)

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
metallo-sulfur cluster assembly	1
nucleic acid binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1046 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IBA57	ISCA2	Q86U28	995
IBA57	ISCA1	Q9BUE6	992
IBA57	NFU1	Q9UMS0	896
IBA57	BOLA3	Q53S33	875
IBA57	LIAS	O43766	846
IBA57	GLRX5	Q86SX6	811
IBA57	LYRM4	Q9HD34	811
IBA57	ISCU	Q9H1K1	808
IBA57	FDX2	Q6P4F2	806
IBA57	NFS1	Q9Y697	794
IBA57	NUBPL	Q8TB37	786
IBA57	BOLA1	Q9Y3E2	746
IBA57	FXN	Q16595	710
IBA57	ABCB7	O75027	709
IBA57	ACO2	Q99798	707

IntAct

59 interactions, top by confidence:

A	B	Type	Score
ISCA2	IBA57	psi-mi:“MI:0407”(direct interaction)	0.860
IBA57	ISCA2	psi-mi:“MI:0407”(direct interaction)	0.860
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
MRRF	DBT	psi-mi:“MI:0914”(association)	0.620
EIF4A1	EIF3D	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
ISCA2	SLMAP	psi-mi:“MI:0914”(association)	0.530
MCEE	CLUH	psi-mi:“MI:0914”(association)	0.530
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
GTF2E2	UBA6	psi-mi:“MI:0914”(association)	0.350
OXLD1	NUDT19	psi-mi:“MI:0914”(association)	0.350
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350
ARHGAP22	KDM6A	psi-mi:“MI:0914”(association)	0.350
LUC7L	CASC3	psi-mi:“MI:0914”(association)	0.350
TMEM184A	NRDC	psi-mi:“MI:0914”(association)	0.350
NIT1	NDUFS6	psi-mi:“MI:0914”(association)	0.350

BioGRID (109): IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), C1orf123 (Co-fractionation), IBA57 (Co-fractionation), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS), IBA57 (Affinity Capture-MS)

ESM2 similar proteins: A2AI05, O08760, O15527, O55240, O70249, O88587, P21139, P50336, P51175, P56602, Q0P5F0, Q14CH1, Q1JP61, Q2TBI8, Q3T0A0, Q497B8, Q4R5N9, Q501J2, Q5E9V4, Q5H879, Q5NVF6, Q5REP0, Q5RK23, Q5T440, Q60HD5, Q6AYG0, Q6P3E7, Q6P9U1, Q8BNV1, Q8BZG5, Q8IZ69, Q8N371, Q8N9H8, Q8VCA8, Q91W89, Q91WM2, Q92781, Q969S8, Q96EN8, Q96FB5

Diamond homologs: A1CBI9, A1DDV0, A2R472, A4R8F9, B8JMH0, P0CM52, P0CM53, Q09929, Q0UE25, Q1DK38, Q2H6N9, Q2U664, Q4P7A4, Q4WVK5, Q5T440, Q6C8Y7, Q75D53, Q7RYZ1, Q8CAK1, A5DQ50, Q54NS1, Q6BPW7, Q8L733, A1AF88, A1JPM8, A4TIB4, A4WE49, A5F5F3, A7FF28, A7MR73, A7MTS4, A7ZR07, A8A439, A8GIQ4, A9MRH6, A9N3M5, A9R4L4, B1ITA4, B1JNT4, B1LD99

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IBA57	“form complex”	“ISCA2-IBA57 mitochondrial iron-sulfur protein assembly complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	11
Uncertain significance	163
Likely benign	106
Benign	8

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073739	NM_001010867.4(IBA57):c.265_286dup (p.Tyr96fs)	Pathogenic
1202371	NM_001010867.4(IBA57):c.307C>T (p.Gln103Ter)	Pathogenic
1396845	NM_001010867.4(IBA57):c.335T>A (p.Leu112Ter)	Pathogenic
1806117	NM_001010867.4(IBA57):c.292del (p.His98fs)	Pathogenic
1968141	NM_001010867.4(IBA57):c.193_203dup (p.Phe69fs)	Pathogenic
1997279	NM_001010867.4(IBA57):c.74_75del (p.Ala25fs)	Pathogenic
203449	NM_001010867.4(IBA57):c.678A>G (p.Gln226=)	Pathogenic
2062660	NM_001010867.4(IBA57):c.454G>T (p.Glu152Ter)	Pathogenic
2187516	NM_001010867.4(IBA57):c.143G>A (p.Trp48Ter)	Pathogenic
2674639	NM_001010867.4(IBA57):c.569_579del (p.Arg190fs)	Pathogenic
2933389	NM_001010867.4(IBA57):c.284_285insT (p.Tyr96fs)	Pathogenic
3761618	NM_001010867.4(IBA57):c.339C>G (p.Tyr113Ter)	Pathogenic
545646	NM_001010867.4(IBA57):c.586T>G (p.Trp196Gly)	Pathogenic
545647	NM_001010867.4(IBA57):c.686C>T (p.Pro229Leu)	Pathogenic
545648	NM_001010867.4(IBA57):c.706C>T (p.Pro236Ser)	Pathogenic
545649	NM_001010867.4(IBA57):c.286T>C (p.Tyr96His)	Pathogenic
545651	NM_001010867.4(IBA57):c.697C>T (p.Arg233Ter)	Pathogenic
545653	NM_001010867.4(IBA57):c.940C>T (p.Gln314Ter)	Pathogenic
545654	NM_001010867.4(IBA57):c.150C>A (p.Cys50Ter)	Pathogenic
56829	NM_001010867.4(IBA57):c.941A>C (p.Gln314Pro)	Pathogenic
660906	NM_001010867.4(IBA57):c.384dup (p.Asp129Ter)	Pathogenic
972915	NM_001010867.4(IBA57):c.589_590del (p.Arg197fs)	Pathogenic
1067695	NM_001010867.4(IBA57):c.341+1G>T	Likely pathogenic
2130852	NM_001010867.4(IBA57):c.342-488_361del	Likely pathogenic
2136152	NM_001010867.4(IBA57):c.285delinsTA (p.Tyr96fs)	Likely pathogenic
2585593	NM_001010867.4(IBA57):c.24del (p.Gly9fs)	Likely pathogenic
2674638	NM_001010867.4(IBA57):c.310G>T (p.Gly104Cys)	Likely pathogenic
2940344	NM_001010867.4(IBA57):c.341+2T>G	Likely pathogenic
522951	NM_001010867.4(IBA57):c.313C>T (p.Arg105Trp)	Likely pathogenic
545652	NM_001010867.4(IBA57):c.323A>C (p.Tyr108Ser)	Likely pathogenic

SpliceAI

653 predictions. Top by Δscore:

Variant	Effect	Δscore
1:228166156:GG:G	donor_gain	1.0000
1:228166157:GG:G	donor_gain	1.0000
1:228166158:G:GG	donor_gain	0.9900
1:228166158:G:T	donor_loss	0.9900
1:228175026:CAAGG:C	donor_loss	0.9900
1:228175028:AGGT:A	donor_loss	0.9900
1:228175029:GGT:G	donor_loss	0.9900
1:228175030:G:T	donor_loss	0.9900
1:228175031:T:G	donor_loss	0.9900
1:228175353:G:GT	donor_gain	0.9900
1:228166153:TACGG:T	donor_gain	0.9800
1:228175259:G:GT	donor_gain	0.9800
1:228174954:G:GT	donor_gain	0.9700
1:228166152:G:GG	donor_gain	0.9600
1:228174687:TGCA:T	acceptor_loss	0.9600
1:228174689:CA:C	acceptor_loss	0.9600
1:228174690:AGGCT:A	acceptor_loss	0.9600
1:228175121:GGC:G	acceptor_gain	0.9600
1:228175330:TGCC:T	donor_gain	0.9600
1:228175340:C:CG	donor_gain	0.9600
1:228175354:A:T	donor_gain	0.9600
1:228175357:GACT:G	donor_gain	0.9600
1:228174690:AG:A	acceptor_gain	0.9500
1:228174691:GG:G	acceptor_gain	0.9500
1:228175332:CCACG:C	donor_gain	0.9500
1:228175511:T:TA	donor_gain	0.9500
1:228175512:A:AA	donor_gain	0.9500
1:228174690:A:AG	acceptor_gain	0.9400
1:228174691:G:GG	acceptor_gain	0.9400
1:228175025:GCAAG:G	donor_gain	0.9400

AlphaMissense

2231 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:228175212:A:T	K257I	0.990
1:228175231:G:C	Q263H	0.984
1:228175231:G:T	Q263H	0.984
1:228175287:T:A	V282D	0.981
1:228166040:C:T	T75I	0.980
1:228175245:G:C	R268P	0.980
1:228166130:G:C	R105P	0.979
1:228175205:T:C	F255L	0.976
1:228175207:C:A	F255L	0.976
1:228175207:C:G	F255L	0.976
1:228175180:C:A	N246K	0.974
1:228175180:C:G	N246K	0.974
1:228175213:A:C	K257N	0.970
1:228175213:A:T	K257N	0.970
1:228174940:G:C	R197P	0.968
1:228175175:T:C	S245P	0.968
1:228175493:T:A	W351R	0.968
1:228175493:T:C	W351R	0.968
1:228174729:G:A	E127K	0.967
1:228175227:G:T	G262V	0.967
1:228174913:A:T	D188V	0.966
1:228175018:G:C	R223P	0.966
1:228175275:G:C	R278P	0.966
1:228175233:A:T	E264V	0.965
1:228174913:A:C	D188A	0.964
1:228175227:G:A	G262D	0.964
1:228175241:G:C	A267P	0.963
1:228175490:T:A	W350R	0.963
1:228175490:T:C	W350R	0.963
1:228175234:G:C	E264D	0.960

dbSNP variants (sampled 300 via entrez): RS1000059407 (1:228173817 C>T), RS1000132634 (1:228175684 A>G), RS1000298503 (1:228170573 A>C), RS1000394980 (1:228164609 G>A), RS1000447237 (1:228164793 G>A), RS1001097702 (1:228180963 G>C), RS1001265674 (1:228177961 CT>C), RS1001274661 (1:228168091 G>C), RS1001372628 (1:228173260 G>A), RS1001759352 (1:228178244 T>C), RS1002173815 (1:228173098 G>A), RS1002348628 (1:228167514 G>A), RS1002383808 (1:228174482 T>C,G), RS1002399733 (1:228182476 A>C,G), RS1002617439 (1:228166071 CGCGG>C)

Disease associations

OMIM: gene MIM:615316 | disease phenotypes: MIM:615330, MIM:616451

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple mitochondrial dysfunctions syndrome 3	Strong	Autosomal recessive
hereditary spastic paraplegia 74	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (4): multiple mitochondrial dysfunctions syndrome 3 (MONDO:0014132), hereditary spastic paraplegia 74 (MONDO:0014644), breast ductal adenocarcinoma (MONDO:0005590), microcephaly (MONDO:0001149)

Orphanet (2): Multiple mitochondrial dysfunctions syndrome type 3 (Orphanet:363424), Autosomal recessive spastic paraplegia type 74 (Orphanet:468661)

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000505	Visual impairment
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000737	Irritability
HP:0001123	Visual field defect
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001258	Spastic paraplegia
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001298	Encephalopathy
HP:0001347	Hyperreflexia
HP:0001511	Intrauterine growth retardation
HP:0001561	Polyhydramnios
HP:0001761	Pes cavus
HP:0001942	Metabolic acidosis
HP:0001954	Recurrent fever
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002093	Respiratory insufficiency
HP:0002119	Ventriculomegaly
HP:0002126	Polymicrogyria
HP:0002154	Hyperglycinemia
HP:0002376	Developmental regression
HP:0002415	Leukodystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1059778	IBA57		0.00	0

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	increases methylation, decreases methylation, affects cotreatment	1
nobiletin	decreases reaction, increases expression	1
sodium arsenate	decreases reaction, increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D2ZC	GM26035	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.