HCCS

Summary

HCCS (holocytochrome c synthase, HGNC:4837) is a protein-coding gene on chromosome Xp22.2, encoding Holocytochrome c-type synthase (P53701). Lyase that catalyzes the covalent linking of the heme group to the cytochrome C apoprotein to produce the mature functional cytochrome. It is a selective cancer dependency (DepMap: 10.2% of cell lines).

The protein encoded by this gene is an enzyme that covalently links a heme group to the apoprotein of cytochrome c. Defects in this gene are a cause of microphthalmia syndromic type 7 (MCOPS7). Three transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 3052 — RefSeq curated summary.

At a glance

• Gene–disease (curated): linear skin defects with multiple congenital anomalies 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 142 total — 4 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 101
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.2% of screened cell lines
• MANE Select transcript: NM_005333

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4837
Approved symbol	HCCS
Name	holocytochrome c synthase
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Aliases	CCHL
Ensembl gene	ENSG00000004961
Ensembl biotype	protein_coding
OMIM	300056
Entrez	3052

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000321143, ENST00000380762, ENST00000380763, ENST00000882309, ENST00000882310, ENST00000882311, ENST00000911475, ENST00000911476, ENST00000911477, ENST00000941838

RefSeq mRNA: 3 — MANE Select: NM_005333 NM_001122608, NM_001171991, NM_005333

CCDS: CCDS14139

Canonical transcript exons

ENST00000380762 — 7 exons

Exon	Start	End
ENSE00000665154	11114835	11114986
ENSE00000665156	11117267	11117415
ENSE00000665158	11118501	11118620
ENSE00000665160	11120907	11120993
ENSE00000854564	11112019	11112160
ENSE00001486158	11111332	11111518
ENSE00003847130	11121612	11123086

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 93.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.5936 / max 123.6415, expressed in 1813 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195486	18.9764	1812
195487	0.6172	223

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.04	gold quality
biceps brachii	UBERON:0001507	92.70	gold quality
gastrocnemius	UBERON:0001388	92.13	gold quality
muscle of leg	UBERON:0001383	92.06	gold quality
muscle organ	UBERON:0001630	91.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.78	gold quality
heart right ventricle	UBERON:0002080	91.76	gold quality
mucosa of transverse colon	UBERON:0004991	91.74	gold quality
esophagus squamous epithelium	UBERON:0006920	91.32	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.31	gold quality
skeletal muscle tissue	UBERON:0001134	91.23	gold quality
vastus lateralis	UBERON:0001379	91.22	gold quality
quadriceps femoris	UBERON:0001377	90.80	gold quality
deltoid	UBERON:0001476	90.67	gold quality
heart left ventricle	UBERON:0002084	90.67	gold quality
cardiac ventricle	UBERON:0002082	90.50	gold quality
muscle tissue	UBERON:0002385	90.42	gold quality
epithelium of esophagus	UBERON:0001976	90.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.95	gold quality
stromal cell of endometrium	CL:0002255	89.94	gold quality
myocardium	UBERON:0002349	89.83	gold quality
palpebral conjunctiva	UBERON:0001812	89.74	gold quality
monocyte	CL:0000576	89.69	gold quality
right atrium auricular region	UBERON:0006631	89.51	gold quality
tibialis anterior	UBERON:0001385	89.40	gold quality
mononuclear cell	CL:0000842	89.36	gold quality
leukocyte	CL:0000738	89.31	gold quality
cardiac atrium	UBERON:0002081	89.26	gold quality
left ventricle myocardium	UBERON:0006566	89.19	gold quality
heart	UBERON:0000948	89.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

74 targeting HCCS, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4425	100.00	67.59	1049
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4470	99.66	69.35	1767

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• Through the study of genetically engineered mice, the loss of HCCS is demonstrated to cause the male lethality of microphthalmia with linear skin defects (MLS) syndrome. (PMID:12444108)
• mutant proteins (R217C and Delta 197-268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS (PMID:17033964)
• Missense mutation p.E159K of HCCS, leading to loss-of-function of encoded holocytochrome c-type synthase, in female with microphthalmia of both eyes and bilateral sclerocornea may suggest HCCS as candidate for severe ocular manifestations. (PMID:17893649)
• Spectroscopic analyses of HCCS alone and complexes of HCCS with site-directed variants of cytochrome c revealed the fundamental steps of heme attachment and maturation. (PMID:23150584)
• Identification of a deletion in two patients, including HCCS, leads to the diagnosis of microphthalmia with linear skin defects syndrome (PMID:23401659)
• These data indicate that heme contacts mediated by residues within these domains modulate the dynamics of heme binding and contribute to the stability of the HCCS-heme-cytochrome c steady state ternary complex. (PMID:25054239)
• cysteines and histidine of the heme attachment site, Cys-XX-Cys-His play a key role in mitochondrial holocytochrome c synthase (PMID:25170082)
• Bacterial cyt c biogenesis pathways (Systems I and II) appear to recognize simply the CXXCH motif, not requiring alpha helix-1. Results here explain mechanistically how HCCS (System III) requires an extended region adjacent to CXXCH for maturation. (PMID:27387500)
• Data suggest that although HCCS mediates heme attachment to N-terminal cysteine in heme-attachment site (CXXXH) of cytochrome C variants, up to 50% of cytochrome C produced is modified in an oxygen-dependent manner, resulting in a mixed population of cytochrome c. [HCCS = holocytochrome c synthase] (PMID:28617588)
• The implication of holocytochrome c synthase mutation in Korean familial hypoplastic amelogenesis imperfecta. (PMID:35243551)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	hccsa.1	ENSDARG00000028131
danio_rerio	hccsa.2	ENSDARG00000095776
danio_rerio	hccsb	ENSDARG00000099358
mus_musculus	Hccs	ENSMUSG00000031352
rattus_norvegicus	Hccs	ENSRNOG00000025910
drosophila_melanogaster	Cchl	FBGN0038925
caenorhabditis_elegans		WBGENE00011527

Protein

Protein identifiers

Holocytochrome c-type synthase — P53701 (reviewed: P53701)

Alternative names: Cytochrome c-type heme lyase

All UniProt accessions (1): P53701

UniProt curated annotations — full annotation on UniProt →

Function. Lyase that catalyzes the covalent linking of the heme group to the cytochrome C apoprotein to produce the mature functional cytochrome.

Subcellular location. Mitochondrion inner membrane. Membrane.

Disease relevance. Linear skin defects with multiple congenital anomalies 1 (LSDMCA1) [MIM:309801] A disorder characterized by dermal, ocular, neurological and cardiac abnormalities. LSDMCA1 main features are unilateral or bilateral microphthalmia, linear skin defects in affected females, and in utero lethality for males. Skin defects are limited to the face and neck, consisting of areas of aplastic skin that heal with age to form hyperpigmented areas. Additional features in female patients include agenesis of the corpus callosum, sclerocornea, chorioretinal abnormalities, infantile seizures, congenital heart defect, intellectual disability, and diaphragmatic hernia. Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the cytochrome c-type heme lyase family.

RefSeq proteins (3): NP_001116080, NP_001165462, NP_005324* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000511	Holocyt_c/c1_synthase	Family

Pfam: PF01265

Enzyme classification (BRENDA):

• EC 4.4.1.17 — Holocytochrome-c synthase (BRENDA: 8 organisms, 26 substrates, 7 inhibitors, 1 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• holo-[cytochrome c] = apo-[cytochrome c] + heme b (RHEA:22648)

UniProt features (11 total): mutagenesis site 2, repeat 2, sequence variant 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53701-F1	78.84	0.54

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): 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
211	no effect on holocytochrome c synthase activity.
154	loss of holocytochrome c synthase activity. loss of heme-binding. loss of interaction with cytochrome c.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism

MSigDB gene sets: 361 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, ENK_UV_RESPONSE_KERATINOCYTE_UP, MORF_UBE2N, MORF_HDAC2, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_PROTEIN_MATURATION, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_ELECTRON_TRANSPORT_CHAIN, MORF_BUB3, MORF_RFC4, GOCC_MITOCHONDRIAL_ENVELOPE, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN

GO Biological Process (3): animal organ morphogenesis (GO:0009887), cytochrome c-heme linkage (GO:0018063), respiratory electron transport chain (GO:0022904)

GO Molecular Function (5): holocytochrome-c synthase activity (GO:0004408), heme binding (GO:0020037), metal ion binding (GO:0046872), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
anatomical structure morphogenesis	1
animal organ development	1
protein-heme linkage	1
cytochrome complex assembly	1
electron transport chain	1
cellular respiration	1
carbon-sulfur lyase activity	1
catalytic activity, acting on a protein	1
tetrapyrrole binding	1
cation binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1

Protein interactions and networks

STRING

1948 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCCS	ARHGAP6	O43182	925
HCCS	CYCS	P00001	749
HCCS	CYC1	P08574	627
HCCS	GPM6B	Q13491	602
HCCS	NTNG2	Q96CW9	588
HCCS	NTNG1	Q9Y2I2	580
HCCS	GLRA2	P23416	548
HCCS	TTC19	Q6DKK2	548
HCCS	GLUD2	P49448	546
HCCS	GRPR	P30550	546
HCCS	GDI1	P31150	543
HCCS	CCS	O14618	541
HCCS	B3GLCT	Q6Y288	540
HCCS	COX7B	P24311	512
HCCS	ATOX1	O00244	505

IntAct

117 interactions, top by confidence:

A	B	Type	Score
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
TADA1	TAF5L	psi-mi:“MI:0914”(association)	0.640
HCCS	AGK	psi-mi:“MI:0915”(physical association)	0.620
AGK	HCCS	psi-mi:“MI:0914”(association)	0.620
ASCC3	HCCS	psi-mi:“MI:0915”(physical association)	0.560
HCCS	SENP2	psi-mi:“MI:0915”(physical association)	0.560
HCCS	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
HCCS	SNX1	psi-mi:“MI:0915”(physical association)	0.560
CCK	HCCS	psi-mi:“MI:0915”(physical association)	0.560
SH3GLB1	HCCS	psi-mi:“MI:0915”(physical association)	0.560
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
IFNA21	IFIT3	psi-mi:“MI:0914”(association)	0.530
IFNA13	IFNA21	psi-mi:“MI:0914”(association)	0.530
C1orf220	HCCS	psi-mi:“MI:0914”(association)	0.530
FZR1	TK1	psi-mi:“MI:0914”(association)	0.530
HCCS	NPAT	psi-mi:“MI:0914”(association)	0.530
CHCHD5	HCCS	psi-mi:“MI:0915”(physical association)	0.500
CLRN3	HCCS	psi-mi:“MI:0915”(physical association)	0.400
HCCS	MROH1	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
ORF28	PEX19	psi-mi:“MI:0914”(association)	0.350

BioGRID (174): FZR1 (Affinity Capture-MS), ARMCX3 (Affinity Capture-MS), PHF23 (Affinity Capture-MS), NPAT (Affinity Capture-MS), CYC1 (Affinity Capture-MS), KCNQ5 (Affinity Capture-MS), MTCH2 (Affinity Capture-MS), GPATCH8 (Affinity Capture-MS), MID1IP1 (Affinity Capture-MS), MRRF (Affinity Capture-MS), MPZL1 (Affinity Capture-MS), METTL16 (Affinity Capture-MS), MARCH7 (Affinity Capture-MS), HCCS (Affinity Capture-MS), HCCS (Affinity Capture-MS)

ESM2 similar proteins: A1CT57, A1DMG9, A1L243, A4R8D7, A5PJG7, C8V9Y5, F1R777, F7VSU2, I1RMK9, I1RX50, O13962, O96005, P06182, P0CM34, P0CM35, P10871, P14187, P25711, P53700, P53701, P53702, P53703, P9WES7, Q00873, Q04499, Q0J6P7, Q0U388, Q13435, Q14696, Q2NL17, Q2UM19, Q4V8C8, Q4WMU5, Q4WN42, Q51LD2, Q552W5, Q5F339, Q5R6F1, Q5U2R7, Q5ZLM0

Diamond homologs: A5PJG7, O13962, O74794, P06182, P14187, P53700, P53701, P53702, P53703, P9WES7, Q00873, Q552W5, Q5F339

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HCCS	“up-regulates activity”	CYCS	“chemical modification”
HCCS	“up-regulates activity”	“heme b”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	9
Uncertain significance	38
Likely benign	23
Benign	14

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
11670	NM_005333.5(HCCS):c.589C>T (p.Arg197Ter)	Pathogenic
1497198	NM_005333.5(HCCS):c.638G>C (p.Trp213Ser)	Pathogenic
4796505	NC_000023.11:g.(10900001_11120000)del	Pathogenic
58591	GRCh38/hg38 Xp22.2(chrX:11104475-11121622)x3	Pathogenic
11671	NM_005333.5(HCCS):c.649C>T (p.Arg217Cys)	Likely pathogenic
151873	GRCh38/hg38 Xp22.2(chrX:11108228-11121175)x3	Likely pathogenic
3064959	NM_005333.5(HCCS):c.2T>C (p.Met1Thr)	Likely pathogenic
3390915	NM_005333.5(HCCS):c.404G>A (p.Trp135Ter)	Likely pathogenic
3390916	NM_005333.5(HCCS):c.603G>A (p.Trp201Ter)	Likely pathogenic
3390917	NM_005333.5(HCCS):c.650G>A (p.Arg217His)	Likely pathogenic
3390918	NM_005333.5(HCCS):c.715C>T (p.Gln239Ter)	Likely pathogenic
4291739	NM_005333.5(HCCS):c.163del (p.Ala55fs)	Likely pathogenic
987889	NM_005333.5(HCCS):c.308_309insAGT (p.Val103dup)	Likely pathogenic

SpliceAI

1294 predictions. Top by Δscore:

Variant	Effect	Δscore
X:11111353:G:GT	donor_gain	1.0000
X:11111382:G:GT	donor_gain	1.0000
X:11111454:GGCT:G	donor_gain	1.0000
X:11111455:GCT:G	donor_gain	1.0000
X:11114830:TTCA:T	acceptor_loss	1.0000
X:11114832:CA:C	acceptor_loss	1.0000
X:11114833:A:AG	acceptor_gain	1.0000
X:11114833:AG:A	acceptor_gain	1.0000
X:11114834:G:GG	acceptor_gain	1.0000
X:11114834:GG:G	acceptor_gain	1.0000
X:11114834:GGCT:G	acceptor_gain	1.0000
X:11114983:TCTGG:T	donor_loss	1.0000
X:11114984:CTGGT:C	donor_loss	1.0000
X:11114985:TGGTA:T	donor_loss	1.0000
X:11114986:GG:G	donor_loss	1.0000
X:11114987:GTA:G	donor_loss	1.0000
X:11114988:T:G	donor_loss	1.0000
X:11117263:TTAG:T	acceptor_loss	1.0000
X:11117264:TAGAT:T	acceptor_loss	1.0000
X:11117265:A:AG	acceptor_gain	1.0000
X:11117265:A:AT	acceptor_loss	1.0000
X:11117265:AGAT:A	acceptor_gain	1.0000
X:11117266:G:GC	acceptor_gain	1.0000
X:11117266:GAT:G	acceptor_gain	1.0000
X:11117266:GATG:G	acceptor_gain	1.0000
X:11117412:AAGG:A	donor_gain	1.0000
X:11117413:AGG:A	donor_gain	1.0000
X:11117414:GG:G	donor_gain	1.0000
X:11117414:GGG:G	donor_gain	1.0000
X:11117415:GG:G	donor_gain	1.0000

AlphaMissense

1755 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:11118559:C:G	H154D	1.000
X:11121640:T:A	W213R	1.000
X:11121640:T:C	W213R	1.000
X:11117366:T:A	W118R	0.999
X:11117366:T:C	W118R	0.999
X:11117368:G:C	W118C	0.999
X:11117368:G:T	W118C	0.999
X:11117379:C:T	S122F	0.999
X:11117390:T:C	F126L	0.999
X:11117392:C:A	F126L	0.999
X:11117392:C:G	F126L	0.999
X:11118583:T:A	W162R	0.999
X:11118583:T:C	W162R	0.999
X:11118585:G:C	W162C	0.999
X:11118585:G:T	W162C	0.999
X:11118601:T:A	W168R	0.999
X:11118601:T:C	W168R	0.999
X:11120930:T:C	L182S	0.999
X:11121625:T:C	F208L	0.999
X:11121627:T:A	F208L	0.999
X:11121627:T:G	F208L	0.999
X:11121632:G:T	R210M	0.999
X:11121634:C:A	H211N	0.999
X:11121634:C:G	H211D	0.999
X:11121641:G:C	W213S	0.999
X:11121642:G:C	W213C	0.999
X:11121642:G:T	W213C	0.999
X:11117379:C:A	S122Y	0.998
X:11117391:T:C	F126S	0.998
X:11117391:T:G	F126C	0.998

dbSNP variants (sampled 300 via entrez): RS1000009400 (X:11111569 C>T), RS1000111798 (X:11109482 T>C), RS1000162890 (X:11115593 T>G), RS1000392336 (X:11117466 A>C), RS1000979646 (X:11119486 C>G), RS1001151278 (X:11111054 A>G,T), RS1001326764 (X:11119877 T>C,G), RS1001933308 (X:11121873 C>T), RS1002104978 (X:11113227 C>A,T), RS1002333986 (X:11113822 T>C), RS1002385675 (X:11121365 A>T), RS1002453441 (X:11114430 T>C), RS1002984191 (X:11123287 C>G,T), RS1003112885 (X:11115087 C>G,T), RS1003124508 (X:11118928 G>C)

Disease associations

OMIM: gene MIM:300056 | disease phenotypes: MIM:309801, MIM:309800

GenCC curated gene-disease

Disease	Classification	Inheritance
linear skin defects with multiple congenital anomalies 1	Strong	X-linked
linear skin defects with multiple congenital anomalies	Supportive	X-linked

Mondo (4): linear skin defects with multiple congenital anomalies 1 (MONDO:0024552), intellectual disability (MONDO:0001071), syndromic microphthalmia (MONDO:0016073), linear skin defects with multiple congenital anomalies (MONDO:0010672)

Orphanet (3): Microphthalmia with linear skin defects syndrome (Orphanet:2556), Syndromic microphthalmia-anophthalmia-coloboma (Orphanet:202948), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000013	Hypoplasia of the uterus
HP:0000035	Abnormal testis morphology
HP:0000036	Abnormal penis morphology
HP:0000037	Male pseudohermaphroditism
HP:0000039	Epispadias
HP:0000041	Chordee
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000347	Micrognathia
HP:0000363	Abnormal earlobe morphology
HP:0000365	Hearing impairment
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000492	Abnormal eyelid morphology
HP:0000499	Abnormal eyelash morphology
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000528	Anophthalmia
HP:0000556	Retinal dystrophy
HP:0000568	Microphthalmia
HP:0000572	Visual loss
HP:0000580	Pigmentary retinopathy
HP:0000598	Abnormality of the ear
HP:0000612	Iris coloboma
HP:0000614	Abnormal nasolacrimal system morphology

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000477_2	Cognitive performance	1.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537466	Microphthalmia, syndromic 7 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066869 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.05	Kd	88.78	nM	CHEMBL3752910
7.05	ED50	88.78	nM	CHEMBL3752910
6.84	Kd	143.7	nM	CHEMBL5653589
6.84	ED50	143.7	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148491: Binding affinity to human HCCS incubated for 45 mins by Kinobead based pull down assay	kd	0.0888	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148491: Binding affinity to human HCCS incubated for 45 mins by Kinobead based pull down assay	kd	0.1437	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects expression	3
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
beta-methylcholine	affects expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression, increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Oxygen	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Aflatoxin B1	increases expression, decreases methylation	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1
Acrylamide	increases expression	1
Vitamin K 3	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651533	Binding	Binding affinity to human HCCS 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)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders