Prolidase deficiency: it looks like systemic lupus erythematosus but it is not

Abstract

Three siblings with recalcitrant leg ulceration, splenomegaly, photosensitive rash, and autoantibodies were suspected of having prolidase deficiency. Urine was checked for iminodipeptiduria, fibroblasts were cultured and analyzed for prolidase activity, and DNA was extracted for identifying the causative mutation. Glycyl proline was found as the dominant dipeptide in the urine. The activity of proline dipeptidase in fibroblasts was 2.5% of control fibroblasts. Sequence analysis of the PEPD gene revealed a homozygous nonsense C-->G transition at nucleotide 768. In conclusion, prolidase deficiency was diagnosed in siblings with skin ulceration autoantibodies and a lupus-like disease. A novel nonsense mutation was found, associated with the severe outcome of our patients.

Prolidase Deficiency in a Mexican-American Patient Identified by Array CGH Reveals a Novel and the Largest PEPD Gene Deletion

“…For this reason, the carbohydrate-deficient transferrin studies were tested and found negative, ruling out congenital disorders of glycosylation. Notably, SLE has been linked to PD [Bissonnette et al, 1993;Shrinath et al, 1997;Di Rocco et al, 2007] and is associated with multiple mutations [Lupi et al, 2006[Lupi et al, , 2008Falik-Zaccai et al, 2010;Klar et al, 2010;Butbul Aviel et al, 2012]. The mechanistic relationship between these entities is not clear, but a loss of immune tolerance to lupus-associated autoantigens in PD has been hypothesized, leading to positive antinuclear antibodies and other autoantibody testing even in patients without clinical SLE [Kurien et al, 2013].…”

“…It splits imidodipeptides with Cterminal proline or hydroxyproline, making proline available for reutilization in collagen synthesis [Myara et al, 1984;Klar et al, 2010]. In PD, this enzyme has decreased or complete loss of activity, giving rise to imidodipeptiduria and a variety of clinical manifestations.…”

“…To date, ∼ 90 patients with PD have been described, 67 of which have been molecularly characterized revealing 28 distinct mutant alleles [Tanoue et al, 1990[Tanoue et al, , 1991Ledoux et al, 1994Ledoux et al, , 1996Kikuchi et al, 2000;Forlino et al, 2002;Lupi et al, 2004Lupi et al, , 2006Lupi et al, , 2008Hershkovitz et al, 2006;Wang et al, 2006;Falik-Zaccai et al, 2010;Klar et al, 2010;Butbul Aviel et al, 2012;Caselli et al, 2012;Pandit et al, 2013;Besio et al, 2015]. The PEPD gene is over 130 kb long and is comprised of 15 exons.…”

Prolidase

“…It has been reported that an association might have been between prolidase defi ciency and systemic lupus erythematosus (SLE) in literature (9,15). Prolidase defi ciency could be a risk factor for the development of SLE.…”

Prolidase is a critical enzyme for complete gliadin digestion in Tenebrio molitor larvae

“…Some human pathologies have been associated with prolidase. For example, a lack of prolidase activity causes an autosomal recessive disorder, prolidase deficiency (PD), occurring in one to two per million births (Endo et al, 1990;Klar et al, 2010). This disorder is characterized by chronic ulcerative dermatitis, mental retardation, frequent infections, and massive urinary excretion of imidodipeptides (Buist, Strandholm, Bellinger, & Kennaway, 1972;Endo, Matsuda, Ogata, & Tanaka, 1982;Goodman et al, 1968;Kodama et al, 1976;Nakayama et al, 2003;Powell, Rasco, & Maniscalco, 1974;Sheffield, Schlesinger, & Paull, 1997;Uramatsu et al, 2009).…”