Beyond proline shortage: New insights into the pathophysiology of prolidase deficiency

Abstract

Prolidase deficiency is an ultra-rare metabolic disorder caused by pathogenic variants in the PEPD gene, which causes a wide range of symptoms including chronic ulcers, recurrent infections, systemic lupus erythematosus (SLE), facial dysmorphisms and developmental delay. How decreased prolidase activity - thus an inability to cleave C-terminal proline imidodipeptides - eventually causes these symptoms is as yet poorly understood. However, recent research has unveiled additional roles of prolidase in cellular homeostasis, including regulation of important signalling molecules such as TGF-β, VEGF and p53. This study proposes that dysregulation of these pathways leads to impairments in important wound healing processes, which could explain the combination of chronic ulcers, developmental delay and propensity for autoimmunity, with symptoms such as bone deformities and recurrent infections being the result of impaired intracellular signalling. This article provides a more comprehensive understanding of prolidase deficiency and opens the way for developing new therapeutic avenues.