A novel splice acceptor site mutation (IVS11 G > A) of PEPD gene causing prolidase deficiency associated with hyperimmunoglobulinemia E

• Patients present with lower extremity ulceration and elevated immunoglobulin E levels.
• Prolidase enzyme activity was undetectable and PEPD sequence analysis revealed (c.819-1G > A) substitution.
• Comparative there was increased expression of IL-6, STAT and TNF-a in Hyper IgE patient while IL-23 and TNF-a was highly expressed in prolidase deficient.
• To the best of our knowledge, c.819-1G > A is a novel mutation of PEPD gene with the phenotype of PD and hyper IgE. This is the first comparative expressional study of selected inflammatory genes in a PD patient.

Prolidase deficiency is a rare, autosomal-recessive, inborn error of collagen metabolism. We report a 20-year old girl with prolidase deficiency, who presented with spontaneous, refractory, lower extremity ulceration, elevated immunoglobulin E levels (IgE) and normal intellect. Hyperimmunoglobulin E syndrome was considered as a possible diagnosis but Th1 and Th17 T cell subsets were normal. Thin layer chromatography for examination of amino acids in random urine sample revealed proline containing peptides. Prolidase enzyme activity was undetectable in dried blood spots as well as in plasma using glycylproline as substrate. Sequence analysis of PEPD gene revealed a single nucleotide substitution (G > A) at the splice acceptor consensus sequence of AG resulting in AA at 3′ of intron 11 in both the alleles leading to skipping of entire exon 12, frame shift and premature stop codon at 278.Comparative expression profile of selected inflammatory genes was carried out in the index patient with prolidase deficiency and high immunoglobulin E levels, another patient with hyperimmunoglobulin E syndrome and a normal control. Increased expression of IL-23 and TNF-α in prolidase deficient patient while IL-6 and TNF-a in hyperimmunoglobulinemia E patient was noted. This indicates a pro-inflammatory state in hyperimmunoglobulin E syndrome compared to the stable regulatory immunological state in prolidase deficiency. To the best of our knowledge, 819-1G > A is a novel mutation of PEPD gene in patients with prolidase deficiency and elevated immunoglobulin E levels.