Prolidase enzyme is required for extracellular matrix integrity and impacts on postnatal cerebellar cortex development

Insolia, Violetta; Priori, Erica Cecilia; Gasperini, Caterina; Coppa, F.; Cocchia, Marco; Iervasi, Erika; Ferrari, Béatrice; Besio, Roberta; Maruelli, Silvia; Bernocchi, Graziella; Forlino, Antonella; Bottone, Maria Grazia

doi:10.1002/cne.24735

Cited by 7 publications

(6 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A further study confirmed that PD affects neuronal maturation during development of a brain cortex area [85]. Focusing on the cerebellar cortex, thinner collagen fibers and disorganized basement membrane below the pial meninx were described in the same animal model, as well as aberrant cortical granule cell proliferation and migration, associated to defects in brain lamination and, in particular, in maturation of Purkinje neurons and the formation of synaptic contacts [85].…”

Section: Histology Of Patient's and Animal Model's Tissuesmentioning

confidence: 75%

“…A study on the dark-like mice, the animal model for PD with a 4-pb deletion in exon 14, showed an irregular layering of the dendrites above the hippocampal formation compared to the controls, with especially thinner and interrupted pial basal membrane; abnormal cerebellar cortex lobulation and overgrown blood vessels [84]. A further study confirmed that PD affects neuronal maturation during development of a brain cortex area [85]. Focusing on the cerebellar cortex, thinner collagen fibers and disorganized basement membrane below the pial meninx were described in the same animal model, as well as aberrant cortical granule cell proliferation and migration, associated to defects in brain lamination and, in particular, in maturation of Purkinje neurons and the formation of synaptic contacts [85].…”

Section: Histology Of Patient's and Animal Model's Tissuesmentioning

confidence: 86%

“…On the contrary, insulin growth factor, a strong inducer of collagen biosynthesis, upregulated prolidase activity [90,97]. In the animal model, PD affected neuronal maturation, proliferation and migration [85], as well as bone growth and structure [28].…”

Section: Pathophysiology Of Pdmentioning

confidence: 99%

See 2 more Smart Citations

Clinical Genetics of Prolidase Deficiency: An Updated Review

Spodenkiewicz

Cleary

et al. 2020

Biology

View full text Add to dashboard Cite

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.

show abstract

Section: Histology Of Patient's and Animal Model's Tissuesmentioning

confidence: 75%

Section: Histology Of Patient's and Animal Model's Tissuesmentioning

confidence: 86%

See 1 more Smart Citation

Clinical Genetics of Prolidase Deficiency: An Updated Review

Spodenkiewicz

Cleary

et al. 2020

Biology

View full text Add to dashboard Cite

show abstract

“…IQ scores of Pt1 and Pt2 were within the previously reported average for PD patients. The cause of intellectual disability in PD patients is not clear, but a recent study has proposed that PD may affect synaptic neurotransmission [ 42 ]. In addition, the basement membrane of the pial meninges (pBM), which is essential for brain cortical maturation, is predominantly composed of type IV collagen which would be negatively affected by PD due to disruptions in collagen metabolism [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Prolidase deficiency, a rare inborn error of immunity, clinical phenotypes, immunological features, and proposed treatments in twins

Alrumayyan

Slauenwhite

McAlpine

et al. 2022

Allergy Asthma Clin Immunol

View full text Add to dashboard Cite

Background Prolidase deficiency (PD) is an autosomal recessive inborn multisystemic disease caused by mutations in the PEPD gene encoding the enzyme prolidase D, leading to defects in turnover of proline-containing proteins, such as collagen. PD is categorized as a metabolic disease, but also as an inborn error of immunity. PD presents with a range of findings including dysmorphic features, intellectual disabilities, recurrent infections, intractable skin ulceration, autoimmunity, and splenomegaly. Despite symptoms of immune dysregulation, only very limited immunologic assessments have been reported and standard therapies for PD have not been described. We report twin females with PD, including comprehensive immunologic profiles and treatment modalities used. Case presentation Patient 1 had recurrent infections in childhood. At age 13, she presented with telangiectasia, followed by painful, refractory skin ulcerations on her lower limbs, where skin biopsy excluded vasculitis. She had typical dysmorphic features of PD. Next-generation sequencing revealed pathogenic compound heterozygous mutations (premature stop codons) in the PEPD gene. Patient 2 had the same mutations, typical PD facial features, atopy, and telangiectasias, but no skin ulceration. Both patients had imidodipeptiduria. Lymphocyte subset analysis revealed low-normal frequency of Treg cells and decreased frequency of expression of the checkpoint molecule CTLA-4 in CD4+ TEM cells. Analysis of Th1, Th2, and Th17 profiles revealed increased inflammatory IL-17+ CD8+ TEM cells in both patients and overexpression of the activation marker HLA-DR on CD4+ TEM cells, reflecting a highly activated proinflammatory state. Neither PD patient had specific antibody deficiencies despite low CD4+CXCR5+ Tfh cells and low class-switched memory B cells. Plasma IL-18 levels were exceptionally high. Conclusions Immunologic abnormalities including skewed frequencies of activated inflammatory CD4+ and CD8+ TEM cells, decreased CTLA-4 expression, and defects in memory B cells may be a feature of immune dysregulation associated with PD; however, a larger sample size is required to validate these findings. The high IL-18 plasma levels suggest underlying autoinflammatory processes.

show abstract

“…Modifications of collagen structure could also contribute to the skin lesions; electron microscopic studies of PD patients´ apparently normal skin showed decreased size of collagen fibers and smaller and more heterogeneous fibril diameters (Leoni et al, 1987). Additionally, recent studies focusing on the cerebellar cortex showed a possible cellular/molecular basis of the intellectual disability in PD patients: mouse knocked-out for prolidase presented thinner collagen fibers and disorganized basement membrane below the pial meninx, which is required for correct cortical development (Insolia et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Structural analysis of new compound heterozygous variants in PEPD gene identified in a patient with Prolidase Deficiency diagnosed by exome sequencing

et al. 2021

View full text Add to dashboard Cite

Prolidase Deficiency (PD) is an autosomal recessive rare disorder caused by loss or reduction of prolidase enzymatic activity due to variants in the PEPD gene. PD clinical features vary among affected individuals: skin ulcerations, recurrent infections, and developmental delay are common. In this study, we describe a 16-year-old boy with a mild PD phenotype comprising chronic eczema, recurrent infections and elevated IgE. Whole exome sequencing analysis revealed three PEPD variants: c.575T>C p.(Leu192Pro) inherited from the mother, and c.692_694del p.(Tyr231del) and c.1409G>A p.(Arg470His), both inherited from the father. The variant p.(Tyr231del) has been previously characterized by high-resolution X-ray structure analysis as altering protein dynamics/flexibility. In order to study the effects of the other two prolidase variants, we performed site directed mutagenesis purification and crystallization studies. A high-resolution X-ray structure could only be obtained for the p.(Arg470His) variant, which showed no significant structural differences in comparison to WT prolidase. On the other hand, the p.(Leu192Pro) variant led to significant protein destabilization. Hence, we conclude that the maternal p.(Leu192Pro) variant was likely causally associated with the proband´s disease, together with the known pathogenic paternal variant p.(Tyr231del). Our results demonstrated the utility of exome sequencing to perform diagnosis in PD cases with mild phenotype.

show abstract

Prolidase enzyme is required for extracellular matrix integrity and impacts on postnatal cerebellar cortex development

Cited by 7 publications

References 84 publications

Clinical Genetics of Prolidase Deficiency: An Updated Review

Clinical Genetics of Prolidase Deficiency: An Updated Review

Prolidase deficiency, a rare inborn error of immunity, clinical phenotypes, immunological features, and proposed treatments in twins

Structural analysis of new compound heterozygous variants in PEPD gene identified in a patient with Prolidase Deficiency diagnosed by exome sequencing

Contact Info

Product

Resources

About