Submission Details

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.