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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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ZMPSTE24
zinc metallopeptidase STE24
Chromosome 1 Β· 1p34.2
NCBI Gene: 10269Ensembl: ENSG00000084073.10HGNC: HGNC:12877UniProt: A0A6Q8PHG9
125PubMed Papers
22Diseases
0Drugs
37Pathogenic Variants
FUNCTIONAL ROLE
Protease
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
regulation of defense response to virusendopeptidase activityprotein bindingzinc ion bindingmandibuloacral dysplasia with type B lipodystrophyLethal restrictive dermopathyrestrictive dermopathy 1restrictive dermopathy
✦AI Summary

ZMPSTE24 is a transmembrane zinc metalloprotease located on the inner nuclear membrane that catalytically processes prelamin A by proteolytically removing its C-terminal three residues after farnesylation 1. This processing is critical for generating mature lamin A, a nuclear scaffold protein essential for nuclear envelope integrity 2. Beyond its protease function, ZMPSTE24 clears clogged translocons on the endoplasmic reticulum 1. The enzyme also exhibits antiviral activity independently of its proteolytic function by restricting enveloped RNA and DNA viruses including influenza A, Zika, and Ebola through modulation of the IFITM antiviral pathway and membrane fluidity 34. Mutations in ZMPSTE24 cause premature aging diseases including Hutchinson-Gilford Progeria Syndrome (HGPS), mandibuloacral dysplasia-type B, and restrictive dermopathy, characterized by defective prelamin A processing and accumulation 25. In ZMPSTE24-deficient models, prelamin A accumulation triggers cellular senescence in postmitotic muscle through mtDNA release, cGAS-STING activation, and SASP factor secretion 6. Lonafarnib, a farnesyltransferase inhibitor, was FDA-approved to reduce mortality in HGPS and processing-deficient progeroid laminopathies by preventing pathogenic protein farnesylation 7.

Sources cited
1
ZMPSTE24 is a transmembrane metalloprotease that proteolytically removes C-terminal three residues of farnesylated proteins and clears translocons on the endoplasmic reticulum
PMID: 33293369
2
ZMPSTE24 mutations cause progeroid syndromes by disrupting prelamin A processing; diminished processing may drive physiological aging
PMID: 37885131
3
ZMPSTE24 plays an antiviral role in restricting enveloped RNA and DNA viruses
PMID: 28169297
4
ZMPSTE24 controls IFITM antiviral pathway by modulating membrane fluidity to hinder viral breaching of endosomal barrier
PMID: 35283811
5
Defects in prelamin A processing by ZMPSTE24 result in premature aging disorders including HGPS and related progeroid diseases
PMID: 30625386
6
In Zmpste24-/- myofibers, prelamin A accumulation triggers cellular senescence through mtDNA release, cGAS-STING activation, and SASP expression
PMID: 39039044
7
Lonafarnib was FDA-approved to reduce mortality in HGPS and processing-deficient progeroid laminopathies caused by ZMPSTE24 mutations
PMID: 33590450
Disease Associationsβ“˜22
mandibuloacral dysplasia with type B lipodystrophyOpen Targets
0.81Strong
Lethal restrictive dermopathyOpen Targets
0.74Strong
restrictive dermopathy 1Open Targets
0.70Strong
restrictive dermopathyOpen Targets
0.64Moderate
atrial fibrillationOpen Targets
0.42Moderate
Hutchinson-Gilford progeria syndromeOpen Targets
0.38Weak
genetic disorderOpen Targets
0.19Weak
mandibuloacral dysplasiaOpen Targets
0.19Weak
infectionOpen Targets
0.08Suggestive
non-alcoholic fatty liver diseaseOpen Targets
0.06Suggestive
Alopecia universalisOpen Targets
0.06Suggestive
Hypocalcemic vitamin D-dependent ricketsOpen Targets
0.05Suggestive
Hypocalcemic vitamin D-resistant ricketsOpen Targets
0.05Suggestive
hypotrichosis simplexOpen Targets
0.05Suggestive
craniometadiaphyseal dysplasia, wormian bone typeOpen Targets
0.05Suggestive
cleidocranial dysplasia 1Open Targets
0.05Suggestive
Metaphyseal chondrodysplasia, Schmid typeOpen Targets
0.05Suggestive
Schmid metaphyseal chondrodysplasiaOpen Targets
0.05Suggestive
Cole-Carpenter syndromeOpen Targets
0.05Suggestive
CHST3-related skeletal dysplasiaOpen Targets
0.05Suggestive
Mandibuloacral dysplasia with type B lipodystrophyUniProt
Restrictive dermopathy 1UniProt
Pathogenic Variants37
NM_005857.5(ZMPSTE24):c.1085dup (p.Leu362fs)Pathogenic
Mandibuloacral dysplasia with type B lipodystrophy|Lethal tight skin contracture syndrome|not provided|ZMPSTE24-related disorder|Lethal tight skin contracture syndrome;Mandibuloacral dysplasia with type B lipodystrophy|Restrictive dermopathy 1|Autosomal recessive ZMPSTE24-related disorders
β˜…β˜…β˜†β˜†2025β†’ Residue 362
NM_005857.5(ZMPSTE24):c.794A>G (p.Asn265Ser)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 265
NM_005857.5(ZMPSTE24):c.627+1G>CPathogenic
not provided|Lethal tight skin contracture syndrome|Mandibuloacral dysplasia with type B lipodystrophy
β˜…β˜…β˜†β˜†2025
NM_005857.5(ZMPSTE24):c.1204-1G>APathogenic
not provided
β˜…β˜…β˜†β˜†2025
NM_005857.5(ZMPSTE24):c.1133_1137del (p.Gly377_Phe378insTer)Pathogenic
Mandibuloacral dysplasia with type B lipodystrophy|ZMPSTE24-related disorder
β˜…β˜…β˜†β˜†2024β†’ Residue 377
NM_005857.5(ZMPSTE24):c.709G>T (p.Glu237Ter)Pathogenic
not provided|Mandibuloacral dysplasia with type B lipodystrophy;Lethal tight skin contracture syndrome
β˜…β˜…β˜†β˜†2023β†’ Residue 237
NM_005857.5(ZMPSTE24):c.1019G>A (p.Trp340Ter)Pathogenic
not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 340
NM_005857.5(ZMPSTE24):c.50del (p.Lys17fs)Pathogenic
Lethal tight skin contracture syndrome|not provided
β˜…β˜…β˜†β˜†2021β†’ Residue 17
NM_005857.5(ZMPSTE24):c.628-2A>TPathogenic
not provided
β˜…β˜†β˜†β˜†2026
NM_005857.5(ZMPSTE24):c.121C>T (p.Gln41Ter)Pathogenic
Mandibuloacral dysplasia with type B lipodystrophy|not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 41
NM_005857.5(ZMPSTE24):c.1291_1292del (p.Leu431fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 431
NM_005857.5(ZMPSTE24):c.28_29insA (p.Leu10fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 10
NM_005857.5(ZMPSTE24):c.1020G>A (p.Trp340Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 340
NM_005857.5(ZMPSTE24):c.1059+2dupPathogenic
Restrictive dermopathy 1
β˜…β˜†β˜†β˜†2023
NM_005857.5(ZMPSTE24):c.202C>T (p.Arg68Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 68
NM_005857.5(ZMPSTE24):c.1204-2A>GLikely pathogenic
not provided
β˜…β˜†β˜†β˜†2023
NM_005857.5(ZMPSTE24):c.1105C>T (p.Arg369Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 369
NM_005857.5(ZMPSTE24):c.691G>T (p.Glu231Ter)Pathogenic
not provided|Mandibuloacral dysplasia with type B lipodystrophy
β˜…β˜†β˜†β˜†2022β†’ Residue 231
NM_005857.5(ZMPSTE24):c.533T>A (p.Leu178Ter)Pathogenic
Lethal tight skin contracture syndrome
β˜…β˜†β˜†β˜†2022β†’ Residue 178
NM_005857.5(ZMPSTE24):c.475-2A>GPathogenic
not provided
β˜…β˜†β˜†β˜†2022
View on ClinVar β†—
Related Genes
ICMTProtein interaction100%AGPAT2Protein interaction99%SUN1Protein interaction98%FNTAProtein interaction96%FNTBProtein interaction96%RCE1Protein interaction96%
Tissue Expression6 tissues
Brain
100%
Heart
90%
Liver
77%
Lung
54%
Ovary
46%
Bone Marrow
36%
Gene Interaction Network
Click a node to explore
ZMPSTE24ICMTAGPAT2SUN1FNTAFNTBRCE1
PROTEIN STRUCTURE
Preparing viewer…
PDB5SYT Β· 2.00 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
1.08LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.84 [0.66–1.08]
RankingsWhere ZMPSTE24 stands among ~20K protein-coding genes
  • #3,782of 20,598
    Most Researched125 Β· top quartile
  • #1,614of 5,498
    Most Pathogenic Variants37
  • #10,942of 17,882
    Most Constrained (LOEUF)1.08
Genes detectedZMPSTE24
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
A genome-wide CRISPR-based screen identifies
PMID: 33408182
Sci Transl Med Β· 2021
1.00
2
Prelamin A and ZMPSTE24 in premature and physiological aging.
PMID: 37885131
Nucleus Β· 2023
0.90
3
mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.
PMID: 39039044
Cell Death Dis Β· 2024
0.80
4
Lonafarnib: First Approval.
PMID: 33590450
Drugs Β· 2021
0.70
5
A humanized yeast system to analyze cleavage of prelamin A by ZMPSTE24.
PMID: 30625386
Methods Β· 2019
0.60