Clinical Genetics of Prolidase Deficiency: An Updated Review

Abstract

Prolidase is a ubiquitous enzyme that plays a major role in the metabolism of proline-rich proteins. Prolidase deficiency is a rare autosomal recessive inborn metabolic and multisystemic disease, characterized by a protean association of symptoms, namely intellectual disability, recurrent infections, splenomegaly, skin lesions, auto-immune disorders and cytopenia. To our knowledge, no published review has assembled the different clinical data and research studies over prolidase deficiency. The aim of this study is to summarize the actual state of the art from the descriptions of all the patients with a molecular diagnosis of prolidase deficiency reported to date regarding the clinical, biological, histopathological features, therapeutic options and functional studies.

Co‐expression with chaperones can affect protein 3D structure as exemplified by loss‐of‐function variants of human prolidase

“…Despite PD being a rare disease with estimated occurrence of 1-2 cases per million births, more than 30 mutations were associated with PD, OMIM 170100 [17], and new ones are still being identified (Nat alia Duarte Linhares, personal communication). Several studies showed the potential increase in total prolidase activity in cultured fibroblasts [41][42][43][44] and various therapeutic therapies were investigated [9,[45][46][47][48][49][50][51], but to date no efficient treatment was introduced. In recent years, we have structurally characterized wt prolidase [25] and a series of eight single amino acid substitution or deletions [10] and we could show that one of the major causes of loss of function (LOF) was structural destabilization induced by bulky side chains introduced in places of small ones.…”

“…PD is a rare recessive genetic disorder with only a little over a hundred patients diagnosed to date (www.orpha.net; ORPHA: 742). In PD patients, 35 mutations could be mapped to the PEPD gene including 16 missense mutations and nine insertions/ deletions [9]. A series of eight mutations that result in single amino acid deletion or substitution has recently been analyzed by X-ray crystallography.…”

Current Understanding of the Emerging Role of Prolidase in Cellular Metabolism

“…Its enzymatic properties link to the disease known as prolidase deficiency (PD), which is manifested by massive imidodipeptiduria, hard-to-heal wounds, mental retardation, and impaired immune system. To date, no effective PD treatment has been developed [ 3 ]. Moreover, there are reports indicating the clinical relevance of prolidase in collagen metabolism malfunctions [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ], metabolic [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ], and oncological disorders [ 21 , 22 , 23 , 24 , 25 ].…”

Prolidase Deficiency in Very Early Onset Inflammatory Bowel Disease (VEO-IBD)

“…PD is a very rare genetic disorder with fewer than 100 cases reported [1]. It manifests with a variety of clinical features with facial dysmorphism and dermatological manifestations being the most common [1].…”

“…PD is a very rare genetic disorder with fewer than 100 cases reported [1]. It manifests with a variety of clinical features with facial dysmorphism and dermatological manifestations being the most common [1]. Gastrointestinal manifestations with a VEO-IBD like phenotype are rare and have variable response to medical treatment [2,3].…”