PEPD – Prolidase Deficiency

Prolidase deficiency (PD) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in PEPD, the gene encoding the cytosolic dipeptidase prolidase D. Affected individuals exhibit highly variable clinical features, most commonly chronic lower limb skin ulcerations, dysmorphic facial features, recurrent infections, and intellectual disability. Diagnosis relies on detection of reduced prolidase activity in fibroblasts or elevated iminodipeptiduria and confirmation by genetic testing.

Genetic evidence supports a definitive association between PEPD and PD. Over 20 unrelated probands with homozygous or compound heterozygous PEPD variants have been reported across multiple families, demonstrating consistent autosomal recessive segregation (20 families) (PMID:19308961). A representative pathogenic variant, c.551G>A (p.Arg184Gln), was identified in an asymptomatic 11-year-old individual and shown to reduce enzymatic activity to 7.4% of wild type in COS-1 cell assays (PMID:8900231).

The variant spectrum in PEPD is broad and includes missense substitutions (e.g., p.Arg184Gln), nonsense variants (e.g., p.Arg265Ter), small deletions/insertions (e.g., p.Tyr231del), splice-site mutations, and large genomic deletions. No recurrent founder alleles have been universally established, although certain variants (e.g., p.Ser202Phe) show high prevalence in specific populations (PMID:19308961).

Functional studies demonstrate loss‐of‐function as the primary pathogenic mechanism. Transient expression of multiple PEPD mutants in COS-1 cells confirmed that p.Gly278Asp, p.Gly448Arg, and p.Glu453del are enzymatically inactive, whereas p.Arg184Gln retains only partial activity (PMID:8900231). High-resolution crystal structures of variant proteins revealed four mechanisms of inactivation, including disruption of the Mn2+ catalytic center and active-site destabilization (PMID:30066404).

No studies have convincingly disputed the gene–disease association. Phenotypic heterogeneity in siblings sharing the same PEPD genotype suggests the influence of modifier factors beyond the primary enzyme defect.

In summary, the PEPD–prolidase deficiency association meets ClinGen criteria for a definitive gene–disease relationship, supported by robust segregation data, a diverse spectrum of loss-of-function variants, and concordant functional assays. Genetic testing for PEPD variants enables accurate diagnosis, informs prognosis, and guides management of this multisystemic disorder.

Key take-home: Autosomal recessive loss-of-function variants in PEPD cause prolidase deficiency, a clinically heterogeneous disease marked by skin ulceration, immune dysregulation, and neurodevelopmental impairment.

References

• American journal of human genetics • 1996 • Expression and molecular analysis of mutations in prolidase deficiency. PMID:8900231
• American journal of medical genetics. Part B, Neuropsychiatric genetics • 2010 • A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability. PMID:19308961
• American journal of human genetics • 1994 • Four novel PEPD alleles causing prolidase deficiency. PMID:8198124
• The FEBS journal • 2018 • Structural basis for prolidase deficiency disease mechanisms. PMID:30066404

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