Related Experiment Video
Updated: Nov 8, 2025
Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
Structural analysis of new compound heterozygous variants in PEPD gene identified in a patient with Prolidase
Natália D Linhares1,2, Piotr Wilk3,4, Elżbieta Wątor3,4
1Universidade Federal de Minas Gerais, Faculdade de Medicina, Laboratório de Genômica Clínica, Belo Horizonte, MG, Brazil.
Insights
This study identifies a novel cause for mild Prolidase Deficiency (PD) in a teenager, linking a maternal PEPD gene variant (p.Leu192Pro) to disease, alongside a known paternal variant. Whole exome sequencing proved crucial for diagnosis.
Area of Science:
- Genetics
- Biochemistry
- Rare Diseases
Background:
- Prolidase Deficiency (PD) is a rare autosomal recessive disorder affecting the PEPD gene, leading to varied clinical symptoms like skin issues and infections.
- A 16-year-old male presented with a mild PD phenotype, including chronic eczema, recurrent infections, and elevated IgE levels.
Purpose of the Study:
- To investigate the genetic basis of mild Prolidase Deficiency in a patient with a complex PEPD variant profile.
- To characterize the functional impact of novel and known variants in the PEPD gene.
Main Methods:
- Whole exome sequencing was employed to identify PEPD gene variants.
- Site-directed mutagenesis, protein purification, and crystallization studies were performed to assess variant effects.
- High-resolution X-ray crystallography was used to analyze protein structure.
Main Results:
- Three PEPD variants were identified: maternal c.575T>C p.(Leu192Pro) and paternal c.692_694del p.(Tyr231del) and c.1409G>A p.(Arg470His).
- The maternal p.(Leu192Pro) variant caused significant protein destabilization.
- The paternal p.(Arg470His) variant showed no significant structural changes compared to wild-type prolidase.
Conclusions:
- The maternal p.(Leu192Pro) variant, in conjunction with the paternal p.(Tyr231del) variant, is likely responsible for the patient's mild Prolidase Deficiency.
- Whole exome sequencing is a valuable diagnostic tool for Prolidase Deficiency, especially in cases with mild or atypical phenotypes.
Abstract:
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.
More Related Videos
Related Concept Videos
01:35Pedigree Analysis
01:09Epistasis Analysis
01:43Incomplete Dominance