IFRD1

Summary

IFRD1 (interferon related developmental regulator 1, HGNC:5456) is a protein-coding gene on chromosome 7q31.1, encoding Interferon-related developmental regulator 1 (O00458). Could play a role in regulating gene activity in the proliferative and/or differentiative pathways induced by NGF.

This gene is an immediate early gene that encodes a protein related to interferon-gamma. This protein may function as a transcriptional co-activator/repressor that controls the growth and differentiation of specific cell types during embryonic development and tissue regeneration. Mutations in this gene are associated with sensory/motor neuropathy with ataxia. This gene may also be involved in modulating the pathogenesis of cystic fibrosis lung disease. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 3475 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia type 18 (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 101 total
• Phenotypes (HPO): 18
• MANE Select transcript: NM_001550

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5456
Approved symbol	IFRD1
Name	interferon related developmental regulator 1
Location	7q31.1
Locus type	gene with protein product
Status	Approved
Aliases	PC4, TIS7
Ensembl gene	ENSG00000006652
Ensembl biotype	protein_coding
OMIM	603502
Entrez	3475

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 13 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000005558, ENST00000403825, ENST00000417662, ENST00000421296, ENST00000429071, ENST00000432734, ENST00000440625, ENST00000443101, ENST00000445335, ENST00000462155, ENST00000466459, ENST00000470441, ENST00000476927, ENST00000486688, ENST00000489994, ENST00000535603, ENST00000621379, ENST00000674887, ENST00000674915, ENST00000675041, ENST00000675578, ENST00000675717

RefSeq mRNA: 4 — MANE Select: NM_001550 NM_001007245, NM_001197079, NM_001197080, NM_001550

CCDS: CCDS34736, CCDS56504

Canonical transcript exons

ENST00000403825 — 12 exons

Exon	Start	End
ENSE00000717356	112467981	112468115
ENSE00001185344	112462270	112462378
ENSE00001668103	112450460	112450782
ENSE00001934119	112475430	112477203
ENSE00002455171	112456914	112457038
ENSE00002482840	112456002	112456086
ENSE00003460460	112461866	112461916
ENSE00003473822	112458861	112459018
ENSE00003476074	112472219	112472347
ENSE00003487421	112472766	112472861
ENSE00003580730	112462001	112462179
ENSE00003690890	112455763	112455867

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.4201 / max 2608.2974, expressed in 1825 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80532	75.5316	1825
80531	1.8901	667
80535	0.6599	253
80530	0.6181	299
80534	0.2860	88
80533	0.2398	65
80538	0.0694	28
204652	0.0568	30
80527	0.0307	8
80528	0.0230	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.87	gold quality
jejunal mucosa	UBERON:0000399	98.29	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.89	gold quality
choroid plexus epithelium	UBERON:0003911	97.55	gold quality
germinal epithelium of ovary	UBERON:0001304	97.36	gold quality
vena cava	UBERON:0004087	97.30	gold quality
jejunum	UBERON:0002115	96.99	gold quality
amniotic fluid	UBERON:0000173	96.97	gold quality
mucosa of stomach	UBERON:0001199	96.86	gold quality
saphenous vein	UBERON:0007318	96.68	gold quality
adrenal tissue	UBERON:0018303	96.63	gold quality
right lung	UBERON:0002167	96.48	gold quality
ascending aorta	UBERON:0001496	96.27	gold quality
thoracic aorta	UBERON:0001515	96.13	gold quality
aorta	UBERON:0000947	96.11	gold quality
nerve	UBERON:0001021	96.08	gold quality
tibial nerve	UBERON:0001323	96.08	gold quality
popliteal artery	UBERON:0002250	96.08	gold quality
tibial artery	UBERON:0007610	96.07	gold quality
calcaneal tendon	UBERON:0003701	96.06	gold quality
blood vessel layer	UBERON:0004797	95.98	gold quality
omental fat pad	UBERON:0010414	95.94	gold quality
peritoneum	UBERON:0002358	95.92	gold quality
pituitary gland	UBERON:0000007	95.90	gold quality
adenohypophysis	UBERON:0002196	95.84	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.79	gold quality
visceral pleura	UBERON:0002401	95.77	gold quality
pancreas	UBERON:0001264	95.67	gold quality
pleura	UBERON:0000977	95.64	gold quality
cardia of stomach	UBERON:0001162	95.49	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	1427.97
E-MTAB-7052	yes	948.84
E-HCAD-4	yes	30.17
E-GEOD-135922	yes	20.13
E-MTAB-8060	no	1150.88
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6

miRNA regulators (miRDB)

69 targeting IFRD1, 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-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-187-5P	99.74	70.26	1404

Literature-anchored findings (GeneRIF, showing 28)

• PC4/IFRD1 is able to potentiate the transcription of many genes and to inhibit the transcription of few others, thus acting as regulator of transcription, possibly involved in tissue regeneration (PMID:12691737)
• Identification of PC4/IFRD1 as a coactivator of MyoD, a key master gene of muscle development. (PMID:15743821)
• PC4/IFRD1, known to be required for muscle differentiation, coactivates MyoD by relieving the HDAC4-mediated inhibition of MEF2C, as a result of its ability to dose-dependently displace HDAC4 from MEF2C. (PMID:15743821)
• TIS7, a negative regulator of transcriptional activity, represses expression of OPN and beta-catenin/Tcf-4 target genes (PMID:16204248)
• identification of IFRD1 as a modifier of cystic fibrosis lung disease severity (PMID:19242412)
• Sequence conservation, animal models, and protein structure evaluation support the involvement of IFRD1 in SMNA (PMID:19409521)
• IFRD1 mRNA decay stress-sensitive regulation is mediated by an upstream open reading frame (PMID:20080976)
• IFRD1 is an inducer of skeletal muscle regeneration and of satellite cell amplification, by regulating MyoD and NF-kB. (PMID:21127072)
• IFRD1 is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)
• This work provides evidence for the first time of reduced level of IFRD1 protein in murine and human F508del-CFTR airway epithelial cell models. (PMID:21723850)
• IFRD1 expression is systemically up-regulated in CF neutrophils, is linked to the production of ROS, and is modulated by chemokines in CF airway fluids, depending on the IFRD1 genotype. (PMID:23043087)
• This reference (Tirone and Shooter 1989) shows the cloning and the sequence of the original IFRD1 homolog, isolated in rat as NGF-inducible immediate early gene (named PC4). (PMID:2467301)
• This reference shows the cloning and the sequence of the original IFRD1 homolog isolated in rat as nerve growth factor-inducible immediate early gene (named PC4). (PMID:2467301)
• Studied the association between IFRD1 polymorphisms and gastric cancer in a Chinese population. (PMID:25073439)
• PC4 plays essential roles in the transition step from transcription initiation to elongation by binding to melted DNA in collaboration with TFIIEbeta. (PMID:25308091)
• rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape. (PMID:25939412)
• study reveals an EGFR-IFRD1-mediated viral immune evasion mechanism, which can also be exploited by cancer cells (PMID:26055519)
• Results from a study on gene expression variability markers in early-stage human embryos shows that IFRD1 is a putative marker for the 3-day, 8-cell embryo stage. (PMID:26288249)
• rs7817 polymorphism associated with nasal polyposis in cystic fibrosis patients (PMID:26397160)
• this study shows that IFRD1 gene may be associated with pathogenesis of asthma (PMID:27842724)
• This reference shows the cloning and the sequence of the original IFRD1 homolog isolated in mouse as TPA-inducible immediate early gene (named Tis7). (PMID:2797820)
• High IFRD1 colon cancer expression was significantly associated with decreased 5-year patient survival. (PMID:29094309)
• IFRD1 regulates the asthmatic responses of airway via NF-kappaB pathway. (PMID:32992150)
• Insights on the disruption of the complex between human positive coactivator 4 and p53 by small molecules. (PMID:34534740)
• Disrupting the interaction between a p53 gain-of-function mutant and the transcriptional co-activator PC4 reverses drug resistance in cancer cells. (PMID:38664232)
• Functional ablation of PC4/IFRD1 in myoblast cells by sense and antisense strategies as well as by microinjection of PC4/IFRD1 antibodies, inhibits differentiation. (PMID:7756174)
• In the absence of PC4/IFRD1 skeletal muscle differentiation is defective. (PMID:7756174)
• Identification of the IFRD gene family, comprising the two genes PC4 / Tis7 / IFRD1 and SKMc15 / IFRD2, and in situ-hybridization analysis of their expression during developments (PMID:9722946)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ifrd1	ENSDARG00000068708
mus_musculus	Ifrd1	ENSMUSG00000001627
rattus_norvegicus	Ifrd1	ENSRNOG00000050997
drosophila_melanogaster	Ifrd1	FBGN0051694
caenorhabditis_elegans		WBGENE00010232

Paralogs (1): IFRD2 (ENSG00000214706)

Protein

Protein identifiers

Interferon-related developmental regulator 1 — O00458 (reviewed: O00458)

Alternative names: Nerve growth factor-inducible protein PC4

All UniProt accessions (14): O00458, A0A6Q8PF03, A0A6Q8PFA5, A0A6Q8PH75, A0A6Q8PHN0, A4D0U1, C9J311, C9J7U6, C9JA65, C9JK78, C9JLG5, C9JNM6, E9PMY4, H0YEE3

UniProt curated annotations — full annotation on UniProt →

Function. Could play a role in regulating gene activity in the proliferative and/or differentiative pathways induced by NGF. May be an autocrine factor that attenuates or amplifies the initial ligand-induced signal.

Subunit / interactions. Interacts with PSIP1/LEDGF.

Tissue specificity. Expressed in a variety of tissues.

Similarity. Belongs to the IFRD family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00458-1	1	yes
O00458-2	2

RefSeq proteins (4): NP_001007246, NP_001184008, NP_001184009, NP_001541* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006921	Interferon-rel_develop_reg_C	Domain
IPR007701	Interferon-rel_develop_reg_N	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR039777	IFRD	Family

Pfam: PF04836, PF05004

UniProt features (13 total): sequence conflict 6, compositionally biased region 3, chain 1, region of interest 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00458-F1	84.46	0.68

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 371 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_COLLATERAL_SPROUTING, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, WWTAAGGC_UNKNOWN, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, ENK_UV_RESPONSE_KERATINOCYTE_UP, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_GROWTH

GO Biological Process (11): regulation of transcription by RNA polymerase II (GO:0006357), myoblast fate determination (GO:0007518), striated muscle tissue development (GO:0014706), Wnt signaling pathway (GO:0016055), negative regulation of axon extension (GO:0030517), muscle cell differentiation (GO:0042692), skeletal muscle tissue regeneration (GO:0043403), fat cell differentiation (GO:0045444), negative regulation of collateral sprouting (GO:0048671), adipose tissue development (GO:0060612), cell differentiation (GO:0030154)

GO Molecular Function (0):

GO Cellular Component (3): nucleus (GO:0005634), sarcoplasm (GO:0016528), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cell growth	2
negative regulation of developmental growth	2
negative regulation of axonogenesis	2
cell differentiation	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
cell fate determination	1
myoblast fate commitment	1
muscle tissue development	1
cell surface receptor signaling pathway	1
regulation of axon extension	1
axon extension	1
muscle structure development	1
tissue regeneration	1
collateral sprouting	1
regulation of collateral sprouting	1
animal organ development	1
connective tissue development	1
cellular developmental process	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1346 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFRD1	HDAC1	Q13547	774
IFRD1	SIN3B	O75182	754
IFRD1	SAP30	O75446	693
IFRD1	NCOR1	O75376	555
IFRD1	ATF3	P18847	551
IFRD1	SCNN1B	P51168	497
IFRD1	SCNN1A	P37088	490
IFRD1	RELA	Q04206	474
IFRD1	SCNN1G	P51170	473
IFRD1	GADD45B	O75293	467
IFRD1	TP53	P04637	466
IFRD1	ANKMY2	Q8IV38	427
IFRD1	GADD45A	P24522	421
IFRD1	PPP1R3A	Q16821	420
IFRD1	CFTR	P13569	419

IntAct

19 interactions, top by confidence:

A	B	Type	Score
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
KLHL41	IFRD1	psi-mi:“MI:0915”(physical association)	0.370
TCEAL4	USP11	psi-mi:“MI:0914”(association)	0.350
FOXL1	IFRD1	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CD70	GXYLT2	psi-mi:“MI:0914”(association)	0.350
BSCL2	TMEM223	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GYPA	HYKK	psi-mi:“MI:0914”(association)	0.350
DGCR2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
FAM234A	IFRD1	psi-mi:“MI:0914”(association)	0.350
EIF2AK2	IFRD1	psi-mi:“MI:0914”(association)	0.350
MFSD9	PGRMC1	psi-mi:“MI:0914”(association)	0.350
	IPO5	psi-mi:“MI:0914”(association)	0.350
YWHAG	E2F8	psi-mi:“MI:2364”(proximity)	0.270
IFRD1	RIT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (60): IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-RNA), IFRD1 (Two-hybrid), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-RNA), IFRD1 (Affinity Capture-MS), IFRD1 (Affinity Capture-Western), HDAC1 (Affinity Capture-Western)

ESM2 similar proteins: A2VE70, B1AY13, E1C760, E9Q8I9, F4IDJ0, F7AEX0, K8ERU3, O00458, O94915, P0DX19, P19182, P20695, P50851, P59328, Q08AM6, Q12894, Q13362, Q15172, Q1RMS6, Q28651, Q2KI89, Q5R629, Q5S1U6, Q5T2E6, Q5TBA9, Q5ZIW5, Q5ZL91, Q60996, Q66L58, Q68F38, Q68F70, Q6I621, Q6PD03, Q6PD19, Q7TQK1, Q80TR8, Q80W92, Q80WQ2, Q8CIM8, Q8JGR7

Diamond homologs: O00458, P0DX19, P19182, P20695, Q12894, Q5S1U6, Q9D8U0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	5
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

2180 predictions. Top by Δscore:

Variant	Effect	Δscore
7:112455754:A:AG	acceptor_gain	1.0000
7:112455755:C:G	acceptor_gain	1.0000
7:112455758:A:AG	acceptor_gain	1.0000
7:112455758:AATAG:A	acceptor_gain	1.0000
7:112455759:A:G	acceptor_gain	1.0000
7:112455761:A:AG	acceptor_gain	1.0000
7:112455761:A:T	acceptor_loss	1.0000
7:112455761:AG:A	acceptor_gain	1.0000
7:112455761:AGGT:A	acceptor_gain	1.0000
7:112455761:AGGTG:A	acceptor_gain	1.0000
7:112455762:G:GT	acceptor_gain	1.0000
7:112455762:GG:G	acceptor_gain	1.0000
7:112455762:GGT:G	acceptor_gain	1.0000
7:112455762:GGTG:G	acceptor_gain	1.0000
7:112455762:GGTGG:G	acceptor_gain	1.0000
7:112455864:GATG:G	donor_gain	1.0000
7:112455867:GG:G	donor_loss	1.0000
7:112455867:GGTA:G	donor_gain	1.0000
7:112455868:G:GA	donor_loss	1.0000
7:112455868:G:GG	donor_gain	1.0000
7:112455870:A:AG	donor_gain	1.0000
7:112455870:A:G	donor_gain	1.0000
7:112455990:A:AG	acceptor_gain	1.0000
7:112455991:T:G	acceptor_gain	1.0000
7:112455994:T:G	acceptor_gain	1.0000
7:112455999:TA:T	acceptor_loss	1.0000
7:112456000:A:AG	acceptor_gain	1.0000
7:112456000:AG:A	acceptor_gain	1.0000
7:112456001:G:GA	acceptor_gain	1.0000
7:112456001:GG:G	acceptor_gain	1.0000

AlphaMissense

2979 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:112456925:G:T	R99M	1.000
7:112456925:G:C	R99T	0.999
7:112456926:G:C	R99S	0.999
7:112456926:G:T	R99S	0.999
7:112468047:A:G	K325E	0.999
7:112468049:A:C	K325N	0.999
7:112468049:A:T	K325N	0.999
7:112468081:G:C	R336P	0.999
7:112468093:G:C	R340T	0.999
7:112468094:A:C	R340S	0.999
7:112468094:A:T	R340S	0.999
7:112475456:A:C	K431N	0.999
7:112475456:A:T	K431N	0.999
7:112475461:G:C	R433P	0.999
7:112475473:G:C	R437T	0.999
7:112475474:A:C	R437S	0.999
7:112475474:A:T	R437S	0.999
7:112475495:A:C	R444S	0.999
7:112475495:A:T	R444S	0.999
7:112462124:T:A	W248R	0.998
7:112462124:T:C	W248R	0.998
7:112462332:G:A	G287D	0.998
7:112468059:A:G	K329E	0.998
7:112468060:A:T	K329I	0.998
7:112468061:A:C	K329N	0.998
7:112468061:A:T	K329N	0.998
7:112468093:G:T	R340I	0.998
7:112472279:T:A	W368R	0.998
7:112472279:T:C	W368R	0.998
7:112472782:G:C	R396P	0.998

dbSNP variants (sampled 300 via entrez): RS1000054315 (7:112459125 G>T), RS1000137721 (7:112463398 A>G), RS1000171436 (7:112446691 C>G,T), RS1000186879 (7:112465712 G>T), RS1000243068 (7:112470371 T>G), RS1000347266 (7:112429691 G>A), RS1000362603 (7:112471850 T>G), RS1000405446 (7:112458820 C>T), RS1000480162 (7:112457101 A>G), RS1000485086 (7:112436588 C>T), RS1000603279 (7:112422994 G>A,C), RS1000651042 (7:112472111 T>C), RS1000702145 (7:112455419 A>G), RS1000767668 (7:112456780 T>C), RS1000771824 (7:112447814 T>C,G)

Disease associations

OMIM: gene MIM:603502 | disease phenotypes: MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 18	Supportive	Autosomal dominant
hereditary spastic paraplegia	Limited	Autosomal dominant

Mondo (3): Charcot-Marie-Tooth disease (MONDO:0015626), spinocerebellar ataxia type 18 (MONDO:0011834), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (1): Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000365	Hearing impairment
HP:0000639	Nystagmus
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001761	Pes cavus
HP:0002066	Gait ataxia
HP:0002346	Head tremor
HP:0002395	Lower limb hyperreflexia
HP:0002600	Hyporeflexia of lower limbs
HP:0003202	Skeletal muscle atrophy
HP:0003474	Somatic sensory dysfunction
HP:0003477	Peripheral axonal neuropathy
HP:0007141	Sensorimotor neuropathy
HP:0010546	Muscle fibrillation
HP:0030187	Titubation

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000661_11	Mortality in heart failure	9.000000e-06
GCST001663_11	Amyotrophic lateral sclerosis (age of onset)	2.000000e-06
GCST002155_5	Osteoarthritis (hip)	3.000000e-06
GCST009267_11	Dental caries (decayed, missing and filled teeth)	8.000000e-07
GCST010002_260	Refractive error	3.000000e-11
GCST010796_570	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_571	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_572	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_573	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_574	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_575	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004352	mortality
EFO:0004847	age at onset
EFO:0004327	electrocardiography

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C537197	Sensorimotor neuropathy with ataxia, autosomal dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	4
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression, increases expression	4
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression, increases expression	4
Valproic Acid	increases expression, affects expression, affects cotreatment	4
Cyclosporine	increases expression	4
bisphenol A	decreases expression, affects expression	3
Arsenic Trioxide	decreases expression, increases expression	3
Acetaminophen	increases expression, affects cotreatment	3
Estradiol	increases expression	3
Cadmium Chloride	increases expression, decreases expression, increases abundance	3
Particulate Matter	increases expression, decreases expression, affects cotreatment, increases abundance	3
cobaltous chloride	increases expression	2
perfluorooctanoic acid	increases expression	2
Arsenic	affects expression, affects cotreatment, increases abundance, increases expression	2
Cadmium	increases abundance, increases expression	2
Formaldehyde	decreases expression, increases expression	2
Ozone	affects expression, affects cotreatment, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression, decreases expression	2
Tunicamycin	increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1
diethyl maleate	increases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP