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

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.

Further Clinical Delineation of Prolidase Deficiency Associated with c.1103T>G Variant

“…The literature on PD consists mostly of isolated case reports. Pathogenic variants in the PEPD have been reported from widely differing ethnic and geographic origins [8,9,[11][12][13][14][15]. The carrier frequency is especially high in the Druze community.…”

A Case report of rare disease Prolidase deficiency in a 15-year-old Pakistan boy

“…The variant p.(Tyr231del) is altering protein dynamics/flexibility and the p.(Leu192Pro) variant causes protein destabilization. The variant p.(Arg470His), has no significant structural differences 12 . The maternal p.(Leu192Pro) variant and paternal p.(Tyr231del) are together responsible for the proband´s disease.…”

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“…Future whole exome and whole genome studies may help to understand phenotype variability in affected patients and genotype correlations offering clues for future treatments. The hotspot mutations are reported on the 8th, 12th, and 14th exons 12 . So far,93 cases of prolidase deficiency have been reported in the literature 7 .…”