PREPL Gene

Name	prolyl endopeptidase-like
Description	The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPREPL (prolyl endopeptidase‐like protein) belongs to the prolyl oligopeptidase family and is expressed as a cytosolic serine peptidase with a unique carboxy‐terminal domain. Biochemical studies have demonstrated that, despite possessing a reactive catalytic serine residue, PREPL exhibits only minimal hydrolytic activity against conventional peptide substrates, suggesting that its enzyme function may be specialized or that it may exert important nonhydrolytic roles through protein–protein interactions. This atypical enzymatic profile, highlighted by structural homology to oligopeptidase B yet divergent substrate specificity, indicates that PREPL likely participates in regulatory processes beyond classical peptide cleavage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic investigations have implicated PREPL in several contiguous gene deletion syndromes, including hypotonia–cystinuria syndrome and the broader 2p21 deletion syndromes. Loss‐of‐function mutations, splicing defects, or complete deletions involving the PREPL gene have been associated with neonatal hypotonia, poor early feeding, growth hormone deficiency, and subsequent hyperphagia and obesity. Moreover, cases of congenital myasthenic syndrome (CMS22) caused by diverse PREPL variants further underscore its critical role in neuromuscular function. Collectively, these genetic data firmly establish that disruption of PREPL contributes to a spectrum of complex clinical phenotypes, emphasizing its importance in normal development and muscle as well as neuronal physiology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "9"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies exploring neuronal models have broadened our understanding of PREPL by linking its expression levels to critical pathways in protein trafficking, synaptic activity, and mitochondrial function. Lowered PREPL expression has been associated with altered vesicular transport, deficits in synaptic plasticity, and increased production of neurotoxic proteins such as amyloid‐β and phosphorylated Tau, which are key features in Alzheimer’s disease. Furthermore, analyses of missense variants in PREPL indicate that while catalytic (hydrolytic) activity may remain intact, altered protein–protein interactions can disrupt mitochondrial and vesicle‐mediated processes, thereby contributing to the neuromuscular and cognitive impairments observed in affected individuals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Z Szeltner, I Alshafee, T Juhász, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The PREPL A protein, a new member of the prolyl oligopeptidase family, lacking catalytic activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-005-5262-5"}], "href": "https://doi.org/10.1007/s00018-005-5262-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16143824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16143824"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kevin Martens, Rita Derua, Sandra Meulemans, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PREPL: a putative novel oligopeptidase propelled into the limelight."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1515/BC.2006.111"}], "href": "https://doi.org/10.1515/BC.2006.111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16913837"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16913837"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jaak Jaeken, Kevin Martens, Inge Francois, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/498852"}], "href": "https://doi.org/10.1086/498852"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16385448"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16385448"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "B Chabrol, K Martens, S Meulemans, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia-cystinuria syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2007.055475"}], "href": "https://doi.org/10.1136/jmg.2007.055475"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18234729"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18234729"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Chien-Chang Huang, Wun-Shaing Wayne Chang "}, {"type": "b", "children": [{"type": "t", "text": "Cooperation between NRF-2 and YY-1 transcription factors is essential for triggering the expression of the PREPL-C2ORF34 bidirectional gene pair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Mol Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2199-10-67"}], "href": "https://doi.org/10.1186/1471-2199-10-67"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19575798"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19575798"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Luc Régal, Halil Ibrahim Aydin, Anne-Marie Dieltjens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two novel deletions in hypotonia-cystinuria syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2012.06.011"}], "href": "https://doi.org/10.1016/j.ymgme.2012.06.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22796000"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22796000"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Deborah Bartholdi, Reza Asadollahi, Beatrice Oneda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Further delineation of genotype-phenotype correlation in homozygous 2p21 deletion syndromes: first description of patients without cystinuria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.35994"}], "href": "https://doi.org/10.1002/ajmg.a.35994"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23794250"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23794250"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sebastian Silva, Noriko Miyake, Carolina Tapia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The second point mutation in PREPL: a case report and literature review."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s10038-018-0426-y"}], "href": "https://doi.org/10.1038/s10038-018-0426-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29483676"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29483676"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Olga Shchagina, Ludmila Bessonova, Igor Bychkov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes (Basel) (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/genes11070821"}], "href": "https://doi.org/10.3390/genes11070821"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32707643"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32707643"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Mariana Lemos Duarte, Minghui Wang, Ivone Gomes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multiomics Analyses Identify Proline Endopeptidase-Like Protein As a Key Regulator of Protein Trafficking, a Pathway Underlying Alzheimer's Disease Pathogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/molpharm.122.000641"}], "href": "https://doi.org/10.1124/molpharm.122.000641"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37147110"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37147110"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yenthe Monnens, Anastasia Theodoropoulou, Karen Rosier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JCI Insight (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/jci.insight.179276"}], "href": "https://doi.org/10.1172/jci.insight.179276"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39078710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39078710"}]}]}]}
Synonyms	CMS22
Proteins	PPCEL_HUMAN
NCBI Gene ID	9581
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

PREPL has 6,684 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 114 datasets.

Click the + buttons to view associations for PREPL from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

PREPL Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by PREPL gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of PREPL gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of PREPL gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of PREPL gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of PREPL gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of PREPL gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of PREPL gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of PREPL gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of PREPL gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of PREPL gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of PREPL gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of PREPL gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of PREPL gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with PREPL protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with PREPL gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of PREPL gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of PREPL gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of PREPL gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with PREPL gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of PREPL gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing PREPL protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with PREPL protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with PREPL protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of PREPL gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with PREPL gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with PREPL gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with PREPL gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of PREPL protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by PREPL gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving PREPL gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with PREPL gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with PREPL gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with PREPL gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with PREPL gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at PREPL gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of PREPL gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of PREPL gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing PREPL from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of PREPL gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with PREPL gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.