ZMPSTE24

Summary

ZMPSTE24 (zinc metallopeptidase STE24, HGNC:12877) is a protein-coding gene on chromosome 1p34.2, encoding CAAX prenyl protease 1 homolog (O75844). Transmembrane metalloprotease whose catalytic activity is critical for processing lamin A/LMNA on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum.

This gene encodes a member of the peptidase M48A family. The encoded protein is a zinc metalloproteinase involved in the two step post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A. Mutations in this gene have been associated with mandibuloacral dysplasia and restrictive dermopathy.

Source: NCBI Gene 10269 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mandibuloacral dysplasia with type B lipodystrophy (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 233 total — 26 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 216
• Druggable target: yes
• MANE Select transcript: NM_005857

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12877
Approved symbol	ZMPSTE24
Name	zinc metallopeptidase STE24
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	FACE-1, Ste24p, STE24, HGPS, PRO1
Ensembl gene	ENSG00000084073
Ensembl biotype	protein_coding
OMIM	606480
Entrez	10269

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000372759, ENST00000472583, ENST00000474142, ENST00000479131, ENST00000674703, ENST00000675754, ENST00000675937, ENST00000869003, ENST00000869004, ENST00000869005, ENST00000869006, ENST00000869007, ENST00000869008, ENST00000869009

RefSeq mRNA: 1 — MANE Select: NM_005857 NM_005857

CCDS: CCDS449

Canonical transcript exons

ENST00000372759 — 10 exons

Exon	Start	End
ENSE00000540374	40281343	40281527
ENSE00000768290	40267786	40267872
ENSE00000768291	40268419	40268535
ENSE00000768293	40269975	40270127
ENSE00000768295	40271894	40272035
ENSE00000768297	40285925	40286029
ENSE00000768299	40290854	40290997
ENSE00001458580	40292445	40294180
ENSE00001458591	40258236	40258394
ENSE00003503566	40260839	40260985

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.1422 / max 563.2555, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2357	23.1521	1813
2356	3.1829	1519
2354	1.4319	775
2355	0.3753	175

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hair follicle	UBERON:0002073	97.39	gold quality
choroid plexus epithelium	UBERON:0003911	97.21	gold quality
nephron tubule	UBERON:0001231	96.87	gold quality
tibia	UBERON:0000979	96.53	gold quality
germinal epithelium of ovary	UBERON:0001304	96.50	gold quality
ileal mucosa	UBERON:0000331	96.31	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.96	gold quality
colonic mucosa	UBERON:0000317	95.90	gold quality
heart right ventricle	UBERON:0002080	95.90	gold quality
gingival epithelium	UBERON:0001949	95.65	gold quality
islet of Langerhans	UBERON:0000006	95.55	gold quality
gingiva	UBERON:0001828	95.53	gold quality
bronchial epithelial cell	CL:0002328	95.51	gold quality
esophagus squamous epithelium	UBERON:0006920	95.45	gold quality
kidney epithelium	UBERON:0004819	95.44	gold quality
palpebral conjunctiva	UBERON:0001812	95.11	gold quality
squamous epithelium	UBERON:0006914	94.96	gold quality
parietal pleura	UBERON:0002400	94.90	gold quality
pleura	UBERON:0000977	94.86	gold quality
epithelium of bronchus	UBERON:0002031	94.79	gold quality
epithelium of esophagus	UBERON:0001976	94.75	gold quality
visceral pleura	UBERON:0002401	94.71	gold quality
secondary oocyte	CL:0000655	94.70	gold quality
renal glomerulus	UBERON:0000074	94.63	gold quality
metanephric glomerulus	UBERON:0004736	94.58	gold quality
oviduct epithelium	UBERON:0004804	94.56	gold quality
blood vessel layer	UBERON:0004797	94.55	gold quality
bronchus	UBERON:0002185	94.53	gold quality
calcaneal tendon	UBERON:0003701	94.42	gold quality
tongue squamous epithelium	UBERON:0006919	94.42	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.32
E-MTAB-6524	no	68.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

105 targeting ZMPSTE24, 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-6876-5P	100.00	67.68	2126
HSA-MIR-4476	100.00	68.18	2030
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-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-124-3P	99.89	73.74	3043

Literature-anchored findings (GeneRIF, showing 40)

• A premature termination codon mutation in the gene ZMPSTE24 leads to loss of expression of Lamin A as well as abnormal patterns of nuclear sizes and shapes. (PMID:15317753)
• RNA interference of FACE1 protease results in a halt of cell division and accumulation of prelamin A. (PMID:15671064)
• loss causes autosomal recessive restrictive dermopathy (PMID:15843403)
• Restrictive dermopathy is an autosomal recessive laminopathy caused by inactivating ZMPSTE24 mutations that result in defective processing and nuclear accumulation of prelamin A. (PMID:16297189)
• Accumulation of multiple forms of lamin A with down-regulation of FACE-1 suppresses growth in senescent cells. (PMID:17352743)
• darunavir does not inhibit the biochemical activity of ZMPSTE24, nor does it lead to an accumulation of farnesyl-prelamin A in cells. (PMID:18230615)
• ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype. (PMID:18435794)
• inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. (PMID:19351612)
• glu231X mutation of ZMPSTE24 found in unrelated families with diagnosis of restrictive dermopathy and perhaps specific to India (PMID:19383993)
• ZMPSTE24 performs a critical endoproteolytic cleavage step that removes the hydrophobic farnesyl-modified tail of prelamin A. we discuss the discovery of mammalian ZMPSTE24 & review the unexpected connection between ZMPSTE24 and premature aging[review] (PMID:19453269)
• results suggest that LMNA, ZMPSTE24, and LBR sequence variations are not major genetic determinants involved in scleroderma pathogenesis (PMID:19645629)
• study reports on two brothers affected with restrictive dermopathy; compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene (PMID:20101687)
• Data show that mandibuloacral dysplasia associated with ZMPSTE24 mutations has a more severe phenotype than that associated with lamin A mutations. (PMID:20550970)
• ZMPSTE24 mutations are associated with dermopathy. (PMID:20635340)
• In patients with mandibuloacral dysplasia due to ZMPSTE24 mutations, the onset of disease manifestations such as thin skin and micrognathia occurs as early as 5 months of age. (PMID:20814950)
• A report of a novel and a previously reported homozygous null mutation in ZMPSTE24 in two newborns with restrictive dermopathy. (PMID:21108632)
• Three of 87 patients with metabolic syndrome carry a heterozygous mutation in LMNA or in ZMPSTE24. (PMID:21724554)
• Characterization of disease causing mutations in the ZMPSTE24 gene, residual proteolytic activity correlates with disease severity. (PMID:22718200)
• These data implicate copper as an important factor in promoting prostate cancer cell invasion and indicate that the selective posttranslational activation of ZMP-mediated protein shedding might play a role in this process. (PMID:22936788)
• Laminopathy-associated mutations predicted to reduce ZMPSTE24 activity map to the zinc metalloprotease peptide-binding site and to the bottom of the chamber. (PMID:23539603)
• miR-141-3p, which is overexpressed during senescence as a result of epigenetic regulation, is able to decrease ZMPSTE24 expression levels, and leads to an upregulation of prelamin A in human mesenchymal stem cells. (PMID:24101728)
• complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele. (PMID:24169522)
• Here, we report on a familial c.50delA (p.Lys17Serfs*21) mutation of the ZMPSTE24 gene, causing RD in two siblings. (PMID:26379196)
• ZMPSTE24 downregulation is a major contributor in VSMC dysfunctions resulting from LMNA mutations or PI treatments that could translate in early atherosclerosis at the clinical level. (PMID:26724531)
• This case demonstrates that accumulation of prelamin A, independent of the loss of function of ZMPSTE24 metallopeptidase that catalyzes processing of prelamin A, can cause a progeroid disorder and that a cell biology assay could be used in precision medicine to identify a potential therapy. (PMID:27034136)
• results establish that the substrate profile of Ste24p is broader than anticipated, being more similar to that of the M16A protease family than that of the Rce1p CAAX protease with which it has been functionally associated (PMID:27129777)
• the present study suggests that inhibition of ZMPSTE24 by both mutational and expressional pathways might together play a role in tumorigenesis of colorectal cancer and gastric cancer harboring microsatellite instability phenotype. (PMID:27729169)
• used a fluorogenic assay of the activity of purified ZMPSTE24 to demonstrate that HIV protease inhibitors directly inhibit the human enzyme in a manner indicative of a competitive mechanism (PMID:27774687)
• ZMPSTE24 is an important element for innate host defense against a broad spectrum of pathogenic viruses. (PMID:28246125)
• ZMPSTE24 is a downstream effector of IFITM3 and is important for interferon-induced transmembrane antiviral activity. (PMID:28594571)
• ZMPSTE24-dependent cleavage of prelamin A and the eight known disease-associated ZMPSTE24 missense mutations, were examined. (PMID:29794150)
• Together these systems offer powerful methodology to study ZMPSTE24 disease alleles and to dissect the specific residues and features of the lamin A tail that are required for recognition and cleavage by the ZMPSTE24 protease. (PMID:30625386)
• The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24. (PMID:31644822)
• Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology. (PMID:32199981)
• Protein structural and mechanistic basis of progeroid laminopathies. (PMID:32799420)
• ZMPSTE24 Is Associated with Elevated Inflammation and Progerin mRNA. (PMID:32872320)
• OMA1-An integral membrane protease? (PMID:33130089)
• Site specificity determinants for prelamin A cleavage by the zinc metalloprotease ZMPSTE24. (PMID:33293369)
• ZMPSTE24 Regulates SARS-CoV-2 Spike Protein-enhanced Expression of Endothelial PAI-1. (PMID:34003736)
• Restrictive dermopathy: Three new patients with ZMPSTE24 mutations and a review of the literature. (PMID:34647350)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	zmpste24	ENSDARG00000044090
mus_musculus	Zmpste24	ENSMUSG00000043207
rattus_norvegicus	Zmpste24	ENSRNOG00000012054
drosophila_melanogaster	ste24b	FBGN0034175
drosophila_melanogaster	ste24a	FBGN0034176
drosophila_melanogaster	CG7573	FBGN0036153
drosophila_melanogaster	ste24c	FBGN0050462
caenorhabditis_elegans	fce-1	WBGENE00001405

Protein

Protein identifiers

CAAX prenyl protease 1 homolog — O75844 (reviewed: O75844)

Alternative names: Farnesylated proteins-converting enzyme 1, Prenyl protein-specific endoprotease 1, Zinc metalloproteinase Ste24 homolog

All UniProt accessions (4): O75844, A0A6Q8PF67, A0A6Q8PH40, A0A6Q8PHG9

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane metalloprotease whose catalytic activity is critical for processing lamin A/LMNA on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum. Proteolytically removes the C-terminal three residues of farnesylated proteins. Also plays an antiviral role independently of its protease activity by restricting enveloped RNA and DNA viruses, including influenza A, Zika, Ebola, Sindbis, vesicular stomatitis, cowpox, and vaccinia. Mechanistically, controls IFITM antiviral pathway to hinder viruses from breaching the endosomal barrier by modulating membrane fluidity.

Subcellular location. Endoplasmic reticulum membrane. Nucleus inner membrane. Early endosome membrane. Late endosome membrane.

Tissue specificity. Widely expressed. High levels in kidney, prostate, testis and ovary.

Disease relevance. Mandibuloacral dysplasia with type B lipodystrophy (MADB) [MIM:608612] A form of mandibuloacral dysplasia, a rare progeroid disorder with clinical and genetic heterogeneity, characterized by growth retardation, craniofacial dysmorphic features due to distal bone resorption, musculoskeletal and skin abnormalities associated with lipodystrophy. MADB is a disease characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of the cranial suture, joint contractures, and generalized lipodystrophy with loss of subcutaneous fat from the extremities, face, neck and trunk. The disease is caused by variants affecting the gene represented in this entry. Restrictive dermopathy 1 (RSDM1) [MIM:275210] An autosomal recessive form of restrictive dermopathy, a genodermatosis mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial dysmorphism, sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The metalloprotease domain is constituted by the two C-terminal nuclear regions.

Induction. By type I interferon.

Similarity. Belongs to the peptidase M48A family.

RefSeq proteins (1): NP_005848* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001915	Peptidase_M48	Domain
IPR027057	CAXX_Prtase_1	Family
IPR032456	Peptidase_M48_N	Domain

Pfam: PF01435, PF16491

Enzyme classification (BRENDA):

• EC 3.4.24.84 — Ste24 endopeptidase (BRENDA: 7 organisms, 42 substrates, 20 inhibitors, 7 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
K-RAS4B	0.0232–0.0375	4
ABZ-KSKTKC(FARNESYL)VIKD	0.0164	1
ABZ-SEKKDNYIIKGV-(4-NITRO)-Y	0.1125	1
DAEFRHDSGYEVHHQK-(DABCYL)-LVFFAE-(EDANS)-DVGSNK	0.0523	1

UniProt features (60 total): helix 21, topological domain 8, transmembrane region 7, strand 6, turn 6, sequence variant 4, binding site 3, mutagenesis site 2, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5SYT	X-RAY DIFFRACTION	2
4AW6	X-RAY DIFFRACTION	3.4
2YPT	X-RAY DIFFRACTION	3.8
6BH8	X-RAY DIFFRACTION	3.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75844-F1	89.61	0.81

Functional residue map

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

Catalytic / active sites (1): 336

Ligand- & substrate-binding residues (3): 335; 339; 415

Mutagenesis-validated functional residues (2):

Position	Phenotype
335	loss of catalytic activity but not viral restriction.
336	loss of catalytic activity but not viral restriction.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 841 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_CHROMOSOME_ORGANIZATION, ELVIDGE_HYPOXIA_DN, MODULE_52, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, TAATAAT_MIR126, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_BEHAVIOR, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS

GO Biological Process (59): liver development (GO:0001889), hair follicle development (GO:0001942), heart morphogenesis (GO:0003007), ventricular cardiac muscle tissue development (GO:0003229), cardiac ventricle development (GO:0003231), growth plate cartilage development (GO:0003417), DNA repair (GO:0006281), proteolysis (GO:0006508), lipid metabolic process (GO:0006629), inflammatory cell apoptotic process (GO:0006925), nuclear envelope organization (GO:0006998), adult walking behavior (GO:0007628), determination of adult lifespan (GO:0008340), regulation of cell shape (GO:0008360), regulation of autophagy (GO:0010506), regulation of glucose metabolic process (GO:0010906), regulation of lipid metabolic process (GO:0019216), bone mineralization (GO:0030282), prenylated protein catabolic process (GO:0030327), regulation of bone mineralization (GO:0030500), regulation of TOR signaling (GO:0032006), regulation of hormone metabolic process (GO:0032350), multicellular organism growth (GO:0035264), regulation of multicellular organism growth (GO:0040014), maintenance of rDNA (GO:0043007), regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043516), positive regulation of gene expression via chromosomal CpG island demethylation (GO:0044029), regulation of fibroblast proliferation (GO:0048145), thymus development (GO:0048538), regulation of defense response to virus (GO:0050688), neuromuscular process (GO:0050905), protein maturation (GO:0051604), cardiac muscle cell development (GO:0055013), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), kidney morphogenesis (GO:0060993), cardiac conduction (GO:0061337), CAMKK-AMPK signaling cascade (GO:0061762), regulation of stress-activated protein kinase signaling cascade (GO:0070302), cellular response to gamma radiation (GO:0071480), CAAX-box protein processing (GO:0071586)

GO Molecular Function (9): double-stranded DNA binding (GO:0003690), endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), metalloexopeptidase activity (GO:0008235), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (11): nuclear inner membrane (GO:0005637), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), nucleus (GO:0005634), nuclear envelope (GO:0005635), endosome (GO:0005768), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	3
peptidase activity	2
metallopeptidase activity	2
endosome membrane	2
intracellular membrane-bounded organelle	2
gland development	1
hepaticobiliary system development	1
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
heart development	1
animal organ morphogenesis	1
cardiac muscle tissue development	1
cardiac chamber development	1
endochondral bone growth	1
cartilage development involved in endochondral bone morphogenesis	1
connective tissue development	1
DNA metabolic process	1
DNA damage response	1
protein metabolic process	1
primary metabolic process	1
apoptotic process	1
nucleus organization	1
endomembrane system organization	1
membrane organization	1
adult locomotory behavior	1
walking behavior	1
multicellular organismal process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
autophagy	1
regulation of catabolic process	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
lipid metabolic process	1
regulation of primary metabolic process	1
ossification	1
biomineral tissue development	1
modification-dependent protein catabolic process	1

Protein interactions and networks

STRING

2338 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZMPSTE24	RCE1	Q9Y256	986
ZMPSTE24	ICMT	O60725	963
ZMPSTE24	LMNA	P02545	928
ZMPSTE24	BSCL2	Q96G97	802
ZMPSTE24	AGPAT2	O15120	798
ZMPSTE24	SUN1	O94901	783
ZMPSTE24	LMNB1	P20700	774
ZMPSTE24	EMD	P50402	758
ZMPSTE24	SUN2	Q9UH99	734
ZMPSTE24	WRN	Q14191	675
ZMPSTE24	DNAJA1	P31689	662
ZMPSTE24	SYNE1	Q8NF91	653
ZMPSTE24	FNTB	P49356	646
ZMPSTE24	LMNB2	Q03252	622
ZMPSTE24	B4DL54	B4DL54	592

IntAct

121 interactions, top by confidence:

A	B	Type	Score
AKR7A3	AKR7A2	psi-mi:“MI:0914”(association)	0.890
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
PRELID1	TRIAP1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
DEFB4A	ZMPSTE24	psi-mi:“MI:0915”(physical association)	0.590
ZMPSTE24	LMNA	psi-mi:“MI:0407”(direct interaction)	0.560
ZMPSTE24	LMNA	psi-mi:“MI:0570”(protein cleavage)	0.560
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
GJB7	PALM3	psi-mi:“MI:0914”(association)	0.530
SLC2A5	RBFOX3	psi-mi:“MI:0914”(association)	0.530
GDPD5	GOLIM4	psi-mi:“MI:0914”(association)	0.530
TNFRSF17	TSPAN6	psi-mi:“MI:0914”(association)	0.530
TMPRSS12	FZD6	psi-mi:“MI:0914”(association)	0.530
RNF26	NME2P1	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
FDPS	ZMPSTE24	psi-mi:“MI:0914”(association)	0.530
WASHC3	WASH3P	psi-mi:“MI:0914”(association)	0.530
NRM	ZMPSTE24	psi-mi:“MI:0914”(association)	0.530
TNFRSF17	ZMPSTE24	psi-mi:“MI:0914”(association)	0.530
M	ZMPSTE24	psi-mi:“MI:0915”(physical association)	0.500
M2	ZMPSTE24	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (226): ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), CLTC (Co-fractionation), ZMPSTE24 (Proximity Label-MS), ZMPSTE24 (Proximity Label-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS)

ESM2 similar proteins: A0JNC1, A2VE61, B2RZ37, D4A9I3, O75844, O95563, O95674, Q00765, Q0VCK9, Q0VFK3, Q29RM3, Q29S14, Q401C0, Q5BL21, Q5R4Z3, Q5R7B1, Q5R9I4, Q5R9K4, Q5RDV3, Q5RE33, Q5ZKJ0, Q60870, Q68EQ9, Q68EY2, Q6DD32, Q6GM44, Q6INE8, Q6NYY9, Q6P360, Q6P3N5, Q6PBX9, Q80W54, Q8BG21, Q8BXA5, Q8R1Z9, Q91ZQ0, Q940S0, Q96GC9, Q96KA5, Q99KU0

Diamond homologs: O75844, P47154, Q10071, Q2SJQ5, Q3Y6B8, Q54FH7, Q6EPN8, Q80W54, Q8RX88, Q9XVE5, A0PLW0, A0QRJ0, A1UAZ4, A3PUK0, B2HRQ7, Q1BDZ2, Q5YPB8, A1RT82, P40769, A1WC76, A1WH77, B9MFV5, Q21ST3, A0KID0, A1RIL6, A1TV68, A1VSW7, A3D5N7, A4VMI8, A4XVB4, A4Y7X2, A5W758, A6Q7D4, A6SXH1, A6V3R0, A6WPJ1, A8H3J1, A9L578, B0TJN4, B1J4W3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	4
Uncertain significance	78
Likely benign	53
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323784	NM_005857.5(ZMPSTE24):c.1085T>A (p.Leu362Ter)	Pathogenic
1377698	NM_005857.5(ZMPSTE24):c.1085del (p.Leu362fs)	Pathogenic
140509	NM_005857.5(ZMPSTE24):c.1020G>A (p.Trp340Ter)	Pathogenic
140512	NM_005857.5(ZMPSTE24):c.1105C>T (p.Arg369Ter)	Pathogenic
140513	NM_005857.5(ZMPSTE24):c.1204-1G>A	Pathogenic
140517	NM_005857.5(ZMPSTE24):c.1263dup (p.Ala422fs)	Pathogenic
140528	NM_005857.5(ZMPSTE24):c.475-2A>G	Pathogenic
140532	NM_005857.5(ZMPSTE24):c.627+1G>C	Pathogenic
140536	NM_005857.5(ZMPSTE24):c.691G>T (p.Glu231Ter)	Pathogenic
140540	NM_005857.5(ZMPSTE24):c.794A>G (p.Asn265Ser)	Pathogenic
1709555	NM_005857.5(ZMPSTE24):c.533T>A (p.Leu178Ter)	Pathogenic
2192618	NM_005857.5(ZMPSTE24):c.202C>T (p.Arg68Ter)	Pathogenic
288995	NM_005857.5(ZMPSTE24):c.818del (p.Lys273fs)	Pathogenic
30585	NM_005857.5(ZMPSTE24):c.591dup (p.Ile198fs)	Pathogenic
30586	NM_005857.5(ZMPSTE24):c.1349G>A (p.Trp450Ter)	Pathogenic
3254941	NM_005857.5(ZMPSTE24):c.1059+2dup	Pathogenic
3382731	NM_005857.5(ZMPSTE24):c.469C>T (p.Gln157Ter)	Pathogenic
3677629	NM_005857.5(ZMPSTE24):c.628-2A>T	Pathogenic
41412	NM_005857.5(ZMPSTE24):c.584_585del (p.Tyr195fs)	Pathogenic
4271	NM_005857.5(ZMPSTE24):c.1085dup (p.Leu362fs)	Pathogenic
4272	NM_005857.5(ZMPSTE24):c.1018T>C (p.Trp340Arg)	Pathogenic
4275	NM_005857.5(ZMPSTE24):c.743C>T (p.Pro248Leu)	Pathogenic
4276	NM_005857.5(ZMPSTE24):c.715G>T (p.Glu239Ter)	Pathogenic
4706430	NM_005857.5(ZMPSTE24):c.1291_1292del (p.Leu431fs)	Pathogenic
620353	NM_005857.5(ZMPSTE24):c.1097T>G (p.Leu366Ter)	Pathogenic
801467	NM_005857.5(ZMPSTE24):c.1060-6_1085del	Pathogenic
1325372	NM_005857.5(ZMPSTE24):c.960del (p.Lys321fs)	Likely pathogenic
2828120	NM_005857.5(ZMPSTE24):c.1204-2A>G	Likely pathogenic
3382730	NM_005857.5(ZMPSTE24):c.1259_1270dup (p.Lys423_Lys424insThrPheAlaLys)	Likely pathogenic
817405	NM_005857.5(ZMPSTE24):c.1248dup (p.Gln417fs)	Likely pathogenic

SpliceAI

1686 predictions. Top by Δscore:

Variant	Effect	Δscore
1:40260830:A:AG	acceptor_gain	1.0000
1:40260831:T:G	acceptor_gain	1.0000
1:40260833:T:G	acceptor_gain	1.0000
1:40260837:A:AG	acceptor_gain	1.0000
1:40260838:G:GA	acceptor_gain	1.0000
1:40260838:GA:G	acceptor_gain	1.0000
1:40260838:GAGA:G	acceptor_gain	1.0000
1:40260838:GAGAA:G	acceptor_gain	1.0000
1:40260981:GCACT:G	donor_gain	1.0000
1:40260982:CACT:C	donor_gain	1.0000
1:40260983:ACT:A	donor_gain	1.0000
1:40260983:ACTG:A	donor_loss	1.0000
1:40260984:CTG:C	donor_loss	1.0000
1:40260985:TG:T	donor_loss	1.0000
1:40260986:G:GG	donor_gain	1.0000
1:40260987:TGAG:T	donor_loss	1.0000
1:40260988:G:GG	donor_loss	1.0000
1:40260989:AGT:A	donor_loss	1.0000
1:40260990:G:GG	donor_gain	1.0000
1:40267781:TATA:T	acceptor_loss	1.0000
1:40267784:A:AG	acceptor_gain	1.0000
1:40267784:A:T	acceptor_loss	1.0000
1:40267785:G:GC	acceptor_loss	1.0000
1:40267785:G:GG	acceptor_gain	1.0000
1:40267785:GC:G	acceptor_gain	1.0000
1:40267785:GCTT:G	acceptor_gain	1.0000
1:40267785:GCTTA:G	acceptor_gain	1.0000
1:40267872:GGT:G	donor_loss	1.0000
1:40267873:GT:G	donor_loss	1.0000
1:40267874:T:A	donor_loss	1.0000

AlphaMissense

3123 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:40268524:T:C	F155L	1.000
1:40268526:C:A	F155L	1.000
1:40268526:C:G	F155L	1.000
1:40271922:T:A	I219N	1.000
1:40271925:C:A	A220D	1.000
1:40281351:C:A	R260S	1.000
1:40281352:G:C	R260P	1.000
1:40281360:C:G	H263D	1.000
1:40281368:T:A	N265K	1.000
1:40281368:T:G	N265K	1.000
1:40281370:C:A	A266D	1.000
1:40281403:T:A	I277K	1.000
1:40281406:T:A	V278D	1.000
1:40281409:T:C	L279S	1.000
1:40281411:T:C	F280L	1.000
1:40281413:T:A	F280L	1.000
1:40281413:T:G	F280L	1.000
1:40281415:A:T	D281V	1.000
1:40281421:T:C	L283P	1.000
1:40285977:A:T	E336V	1.000
1:40285980:T:C	L337P	1.000
1:40285983:G:A	G338E	1.000
1:40292486:G:C	E415D	1.000
1:40292486:G:T	E415D	1.000
1:40292554:T:C	L438P	1.000
1:40260914:T:C	S67P	0.999
1:40260918:G:C	R68P	0.999
1:40260923:T:G	Y70D	0.999
1:40268500:T:C	F147L	0.999
1:40268502:T:A	F147L	0.999

dbSNP variants (sampled 300 via entrez): RS1000225453 (1:40265848 G>C), RS1000286152 (1:40277923 C>A,T), RS1000325775 (1:40283717 G>A), RS1000427870 (1:40291020 A>G), RS1000501507 (1:40279155 T>C), RS1000714456 (1:40282392 T>C), RS1000759392 (1:40289832 G>C), RS1000873666 (1:40278839 G>A,C), RS1000910796 (1:40264066 T>A,G), RS1001166919 (1:40265063 C>T), RS1001265118 (1:40290416 T>G), RS1001388757 (1:40277641 G>A), RS1001433032 (1:40277377 C>T), RS1001486189 (1:40257693 A>C), RS1001498338 (1:40283677 C>T)

Disease associations

OMIM: gene MIM:606480 | disease phenotypes: MIM:608612, MIM:275210

GenCC curated gene-disease

Disease	Classification	Inheritance
restrictive dermopathy 1	Definitive	Autosomal recessive
lethal restrictive dermopathy	Strong	Autosomal recessive
mandibuloacral dysplasia with type B lipodystrophy	Strong	Autosomal recessive
Hutchinson-Gilford progeria syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mandibuloacral dysplasia with type B lipodystrophy	Definitive	AR
obsolete lethal restrictive dermopathy	Definitive	AR

Mondo (5): mandibuloacral dysplasia with type B lipodystrophy (MONDO:0012074), restrictive dermopathy (MONDO:0031213), restrictive dermopathy 1 (MONDO:0800042), (MONDO:0010143), Hutchinson-Gilford progeria syndrome (MONDO:0008310)

Orphanet (3): Restrictive dermopathy (Orphanet:1662), Mandibuloacral dysplasia (Orphanet:2457), Mandibuloacral dysplasia with type B lipodystrophy (Orphanet:90154)

HPO phenotypes

216 total (30 of 216 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000050	Hypoplastic male external genitalia
HP:0000073	Ureteral duplication
HP:0000134	Female hypogonadism
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000176	Submucous cleft hard palate
HP:0000200	Short lingual frenulum
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000239	Large fontanelles
HP:0000260	Wide anterior fontanel
HP:0000270	Delayed cranial suture closure
HP:0000278	Retrognathia
HP:0000292	Loss of facial adipose tissue
HP:0000316	Hypertelorism
HP:0000320	Bird-like facies
HP:0000331	Short chin
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000418	Narrow nasal ridge
HP:0000436	Abnormal nasal tip morphology
HP:0000444	Convex nasal ridge
HP:0000453	Choanal atresia
HP:0000464	Abnormality of the neck
HP:0000465	Webbed neck
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535706	Mandibuloacral dysplasia with type B lipodystrophy (supp.)
C536920	Tight skin contracture syndrome, lethal (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3739253 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.27	Kd	54.24	nM	CHEMBL5653589
7.27	ED50	54.24	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 46 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149813: Binding affinity to human ZMPSTE24 incubated for 45 mins by Kinobead based pull down assay	kd	0.0542	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
dicrotophos	decreases expression	1
bisphenol A	increases expression	1
CGP 52608	increases reaction, affects binding	1
bisphenol B	increases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Cadmium	increases expression, increases abundance	1
Gold	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Oxygen	decreases expression	1
Ozone	affects expression, increases abundance	1
Piroxicam	decreases expression	1
Quercetin	decreases expression	1
Ribonucleotides	affects binding	1
Rotenone	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	decreases expression	1
Ritonavir	decreases activity	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
CHEMBL3742603	Binding	Inhibition of human FACE1-mediated CaaX protease activity at 10 uM measured every 30 to 60 seconds for 60 mins	8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. — Bioorg Med Chem

Cellosaurus cell lines

16 cell lines: 8 transformed cell line, 5 finite cell line, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1Z15	PSADFN317	Finite cell line	Male
CVCL_1Z16	PSADFN318	Finite cell line	Male
CVCL_1Z19	PSADFN373	Finite cell line	Male
CVCL_1Z20	PSMDFN375	Finite cell line	Female
CVCL_1Z21	PSFDFN376	Finite cell line	Male
CVCL_2A01	PSALBV341	Transformed cell line	Male
CVCL_2A02	PSALBV342	Transformed cell line	Male
CVCL_2A03	PSMLBV343	Transformed cell line	Female
CVCL_2A04	PSFLBV344	Transformed cell line	Male
CVCL_B2LS	Abcam HeLa ZMPSTE24 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00425607	PHASE2	COMPLETED	Phase II Trial of Lonafarnib (a Farnesyltransferase Inhibitor) for Progeria
NCT00731016	PHASE2	COMPLETED	Treatment of the Hutchinson-Gilford Progeria Syndrome With a Combination of Pravastatin and Zoledronic Acid
NCT00879034	PHASE2	COMPLETED	A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
NCT00916747	PHASE2	UNKNOWN	Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
NCT06775041	PHASE2	ACTIVE_NOT_RECRUITING	Study to Determine Optimal Dose and Evaluate Safety, Tolerability, and Pharmacokinetics of Progerinin in Patients With Hutchinson-Gilford Progeria Syndrome (HGPS)
NCT04512963	PHASE1	COMPLETED	Phase I Study of Progerinin in Healthy Volunteers
NCT02579044	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Phase I/II Trial of Everolimus in Combination With Lonafarnib in Progeria
NCT03871972	PHASE1/PHASE2	COMPLETED	Umbilical Cord Blood Transfusion in Progeria Syndrome
NCT00094393	Not specified	COMPLETED	Clinical Studies of Progeria
NCT03895528	Not specified	APPROVED_FOR_MARKETING	Lonafarnib for Patients With Hutchinson-Gilford Progeria Syndrome or Progeroid Laminopathy