PEPD
protein-codingpeptidase D, the group of M24 metallopeptidase family
Gene summary
This gene encodes a member of the peptidase family. The protein forms a homodimer that hydrolyzes dipeptides or tripeptides with C-terminal proline or hydroxyproline residues. The enzyme serves an important role in the recycling of proline, and may be rate limiting for the production of collagen. Mutations in this gene result in prolidase deficiency, which is characterized by the excretion of large amount of di- and tri-peptides containing proline. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~134.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008221
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008221
Submitter: ClinGen
The *PEPD* gene encodes the cytosolic enzyme prolidase. The enzyme specifically cleaves iminodipeptides containing C-terminal proline and hydroxyproline residues found at high levels in collagen. Therefore, it has a pivotal role in collagen metabolism, matrix remodeling and cell growth. PEPD was first described to be involved in prolidase deficiency disease (PD) in 1990 by Tanoue et al (PMID: 2365824). 9 (missense, nonsense, splice site, and insertion-deletion) variants that have been reported in 6 publications are included in this curation (PMIDs: 2365824, 3877262 , 15309682, 35197125, 16470701, 12384772). Over 160 PD patients are described in case studies and patient cohorts, but the genetic evidence reached the maximum points. Mechanism of pathogenicity appears to be biallelic loss of the prolidase enzyme activity. Patients reported showed imidopeptiduria with inconstant association of developmental delay, splenomegaly, repetitive infections, defective wound healing, dermatological lesions, and cytopenia (anemia and thrombocytopenia). Individuals with biallelic missense variants appear to later develop ulcers than individuals with LoF variants (PMID: 34040193). Most patients appear to have evidence of immune dysregulation predisposition with a wide spectrum of clinical and phenotypic heterogeneity including autoimmune disorders (Crohn disease, SLE or lupus-like disorder, psoriatic arthritis, juvenile idiopathic arthritis, autoimmune gastroenteropathies). Other immunological anomalies are also present in a significant number of patients, including hyper IgE, neutropenia, and seldom hypergammaglobulinemia or hypocomplementemia, autoantibodies including antinuclear and anti-dsDNA antibodies, and different cytokines elevated. Recurrent infections including skin and respiratory infections were present in almost half of the patients reported. Another immune phenomenon for which the association with prolidase deficiency is described is HLH (PMID: 34040193). Intrafamilial heterogeneity in the age of onset and severity of symptoms is observed among the reported patients. In addition to sequence analysis of PEPD, diagnosis of PD is based on the determination of prolidase enzyme activity in erythrocytes, leukocytes, and/or skin fibroblast cultures of PD patients or imidodipeptides screening in their urine (PMID: 34532344). The mean time to obtain a diagnosis was 11.6 years in a meta-analysis of over 100 published prolidase deficiency cases (Rossingol et al., PMID: 34040193). Because of the observed founder effect, targeted analysis for the pathogenic variants Arg265Ter in exon 11 and Ser202Phe in exon 8 of the *PEPD* gene might be performed before sequence analysis in certain populations (PMIDs: 26110198 and 32455636). Experimental evidence also supports this gene-disease relationship. PEPD mutant cells showed a markedly reduced enzyme activity compared with the wild-type enzyme (PMID: 15309682). Deficient Prolidase enzyme activity and accumulation of dipeptides resulted in a necrosis-like cell death picture in PEPD mutant fibroblasts, appearing round and branched, with disorganized orientation compared to the tapered shape and parallel orientation seen in control fibroblast cells (PMID: 12384772). Active prolidase could be recovered in prolidase-deficient fibroblasts transfected with a normal human prolidase cDNA (pEPD-W) (PMID: 2365824). There is also evidence of decreased IFNAR1 surface expression and reduced IFNb-stimulated signaling in human PEPD mutant fibroblasts (PMID: 26159719). Pepd-null mice developed systemic lupus erythematosus-like disease (increased antinuclear autoantibodies and raised serum IgA, and kidney immune complex deposition) associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver. The null mice showed spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of Ag receptor specificity or antigenic stimulation (PMID: 36637239). In summary, *PEPD* is definitively associated with Autosomal Recessive Prolidase Deficiency. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time. The PIRD GCEP acknowledges input from Dr. Ivona Aksentijevich (Co-Chair of the RAD CDWG), and Drs. Alexandra Freeman, Anna Pham-Huy and Shefali Samant (Personal Communication) in sharing their experience with patients with prolidase deficiency.
Inheritance Pattern: AR
Disease ID:MONDO:0008221
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008221
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008221
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Biochemical; Craniofacial; Dermatologic; Musculoskeletal; Neurologic
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals may have a number of manifestations, including frequent and severe respiratory and other infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PEPD variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000285.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 203 | 3 | 208 | ||
| missense | 3 | 7 | 228 | 24 | 3 | 265 |
| nonsense | 13 | 2 | 1 | 16 | ||
| start loss | 3 | 3 | ||||
| frameshift | 16 | 6 | 1 | 23 | ||
| splice donor/acceptor (+/-2bp) | 4 | 28 | 4 | 36 | ||
| Total | 36 | 46 | 236 | 227 | 6 | 551 |
Highest pathogenic variant AF is 0.00018311008
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000276.2 | 15 | MANE Select | |
| Ensembl | ENSP00000244137.5 | 15 | MANE Select | |
| RefSeq | NP_001159528.1 | 13 | Standard | |
| RefSeq | NP_001159529.1 | 13 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pepd | Danio rerio | Structure: pancreatic B cell Quality: decreased area abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- proteolysis
- cellular amino acid metabolic process
- collagen catabolic process
Molecular Function
- aminopeptidase activity
- metallocarboxypeptidase activity
- protein binding
- manganese ion binding
- proline dipeptidase activity
Cellular Component
- nucleus
- nucleoplasm
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000244137
- Coding exons
- 15
- Length
- 134845
- Individuals with no LoFs
- 124762
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 44
- Defined
- 124806
- p
- 0.000176
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.180 | 342 | 333 | 1.03 | 0.0000250 | 3198 |
| Missense (PolyPhen) | 116 | 116.56 | 0.9952 | 1055 | ||
| Synonymous | 0.262 | 133 | 137 | 0.971 | 0.0000116 | 963 |
| Loss of Function | 0.527 | 23 | 25.9 | 0.888 | 0.00000132 | 297 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00028 | 0.00026 | rare |
| Latino/Admixed American | 0.00015 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00018 | 0.00017 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00015 | 0.00014 | rare |
| South Asian | 0.00053 | 0.00052 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Splits dipeptides with a prolyl or hydroxyprolyl residue in the C-terminal position. Plays an important role in collagen metabolism because the high level of iminoacids in collagen.;
- Disease
- DISEASE: Prolidase deficiency (PD) [MIM:170100]: A multisystem disorder associated with massive iminodipeptiduria and lack of or reduced prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts. Clinical features include skin ulcers, developmental delay, recurrent infections, and a characteristic facies. {ECO:0000269|PubMed:12384772, ECO:0000269|PubMed:2365824, ECO:0000269|PubMed:8198124, ECO:0000269|PubMed:8900231}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.498
Intolerance Scores
- LoFtool
- 0.298
- RVIS EVS
- -0.15
- RVIS percentile EVS
- 42.28
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.472
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |