Angiopathic pathogenesis of clinical manifestations in prolidase deficiency

Case 1 A 28‐year‐old man presented with his first leg ulcer at the age of 10 years. With regard to the family history, there was no consanguinity between the parents, and the patient had a brother with similar findings. He had frequent infections in childhood, such as otitis media, tuberculosis, and septic arthritis. At the age of 11 years, he showed photosensitivity, malar erythema, and positive antinuclear antibody test (1 : 40), and systemic lupus erythematosus was diagnosed (Fig. 1). This disease was later ruled out because diagnostic criteria were not present. 1 Photosensitivity and malar erythema at the age of 11 years (Case 1) At the age of 12 years, the ulcers worsened and did not respond to different treatments (antimicrobials, prednisone), and a diagnosis of pyoderma gangrenosum was suggested. Nevertheless, histopathology rejected such a diagnosis. The disease progressed until the patient presented again to our department. On examination, the ulcers were located on both legs and thighs, had a polygonal form, elevated borders, and necrotic base (Fig. 2). They showed edema and induration with multiple scars. Dystrophic nails, saddle nose, hypertelorism, syndactyly, obesity, and deformity of the auricle were observed. Laboratory analysis revealed iron deficiency anemia (hematocrit, 30%), an erythrocyte sedimentation rate of 120 mm/h, an elevated gammaglobulin level (3.79 g%), and an elevated immunoglobulin E (IgE) (3285 U/L). Skin cultures were negative. The rest of the laboratory studies were normal (creatinine, glucose, C3, C4, negative HIV, and normal abdominal examination). The evaluation of cellular and humoral immunity showed normal results; chromosome studies disclosed no abnormalities. 2 Polygonal and deep ulcers on the left thigh (Case 1) A skin biopsy showed no specific abnormalities, except fibroblastic proliferation, inflammation, and ulcers that infiltrated the hypodermis. No signs of vasculitis were found. Multiple histologic analyses had been performed throughout the patient's life without any different findings. Aliquots of urine from the patient and controls were analyzed by capillary zone electrophoresis (CZE) according to the method proposed by Zanaboni et al. (Zanaboni G, Grimm KM, Dyne KM, et al. Use of capillary zone electrophoresis for analysis of iminodipeptides in urine of prolidase‐deficient patients. J Chromatogr B 1996; 683: 97–107.) The presence of a large amount of dipeptides, normally absent from control samples, was detected in the patient. There is no specific or effective treatment for prolidase deficiency, but the patient received oral and topical antimicrobials, oral prednisone, 1 mg/kg/day, and thalidomide, 200 mg/day, for 8 months in order to decrease the size of the ulcers and to improve his life quality. Unfortunately, treatment failed. Case 2 The 23‐year‐old younger brother showed his first lesion at the age of 8 years. He had smaller leg ulcers than his brother, but they were pruriginous (Fig. 3). The round ulcers of 2–3 cm in diameter were on the inner part ...

show abstract

“…Histologic studies are not specific. The principal features described are parakeratosis, acanthosis, spongiosis, and lymphocytic infiltration 7 …”

Section: Discussionmentioning

confidence: 99%

Prolidase deficiency: case reports of two Argentinian brothers

et al. 2004

View full text Add to dashboard Cite

show abstract

“…These individuals exhibit defective wound healing resulting in extensive skin ulcerations 13. Of special interest, histologic features on postmortem examination included marked angiopathy not only in skin ulcerations14 but also in internal tissues,15 suggesting that the deficiency in prolidase results in defective angiogenesis. Although these associations are of considerable interest, the mechanisms underlying them are not understood.…”

mentioning

confidence: 99%

Extracellular matrix and HIF‐1 signaling: The role of prolidase

Surażyński

Donald

Cooper

et al. 2007

Intl Journal of Cancer

109

129

View full text Add to dashboard Cite

Hypoxia-inducible factor-1 (HIF-1) plays an important role in stress-responsive gene expression. Although primarily sensitive to hypoxia, HIF-1 signaling can be regulated by a number of stress factors including metabolic stress, growth factors and molecules present in the extracellular matrix (ECM). Degradation of ECM by metalloproteinases (MMP) is important for tumor progression, invasion and metastasis. ECM is predominantly collagen, and the imino acids (Pro and HyPro) comprise 25% of collagen residues. The final step in collagen degradation is catalyzed by prolidase, the obligate peptidase for imidodipeptides with Pro and HyPro in the carboxyl terminus. Defective wound healing in patients with inherited prolidase deficiency is associated with histologic features of angiopathy suggesting that prolidase may play a role in angiogenesis. Because HIF-1a is central to angiogenesis, we considered that prolidase may modulate this pathway. To test this hypothesis, we made expression constructs of human prolidase and obtained stable transfectants in colorectal cancer cells (RKO). Overexpression of prolidase resulted in increased nuclear hypoxia inducible factor (HIF-1a) levels and elevated expression of HIF-12depend-ent gene products, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). The activation of HIF-1-dependent transcription was shown by prolidase-dependent activation of hypoxia response element (HRE)-luciferase expression. We used an oxygen-dependent degradation domain (ODD)-luciferase reporter construct as a surrogate for HIF-1a as an in situ prolyl-hydroxylase assay. Since this reporter is degraded by VHL-dependent mechanisms, the increased levels of luciferase observed with prolidase expression reflected the decreased HIF-1a prolyl hydroxylase activity. Additionally, the differential expression of prolidase in 2 breast cancer cell lines showed prolidase-dependent differences in HIF-1a levels. These findings show that metabolism of imidodipeptides by prolidase plays a previously unrecognized role in angiogenic signaling. ' 2007 Wiley-Liss, Inc.Key words: proline; hypoxia; invasion; extracellular matrix; matrix metalloproteinaseThe transcription factor, hypoxia-inducible factor-1 (HIF-1), plays an important role in stress-responsive gene expression. 1,2 HIF-1 is composed of 2 subunits, HIF-1a and HIF-1b. 1 Its activity is controlled primarily at the level of HIF-1a degradation. 2 The hydroxylation of specific proline residues in the oxygen-dependent degradation domain targets HIF-1a for ubiquitination and proteasomal degradation. In the context of cancer biology, target genes of HIF-1 are upregulated with hypoxic and nutrient stress and mediate angiogenesis, glycolysis, metastasis and survival. 3 HIF-1 signaling responds to decreased oxygen tension, because oxygen is necessary for prolyl hydroxylation and degradation of HIF-1a; 1-3 hypoxia, therefore, stabilizes HIF-1a. However, HIF-1 signaling 1,2 also can be regulated under normoxic conditions by other mechanisms including hormones...

show abstract

“…In the absence of prolidase, the recycling of proline, necessary for the synthesis of new collagen, is blocked and the result is disturbed connective tissue metabolism of the skin and vessels 1,2 . Amorphous vascular deposits, often Congo red‐positive, and ultrastructural changes in collagen molecules have been reported 1–3,9 . Although the pathogenic mechanisms leading to the skin changes are poorly understood, the induction of the release of histamine from isolated mast cells and of collagenase from polymorphonuclear leukocytes by dipeptides containing proline and hydroxyproline, resulting in an inflammatory reaction and ulceration, is a plausible explanation 10 …”

Section: Discussionmentioning

confidence: 99%

Prolidase deficiency

Köktürk¹,

Kaya

İkizoğlu

et al. 2002

Int J Dermatology

View full text Add to dashboard Cite

A 32‐year‐old mentally retarded woman was admitted to hospital with recurrent ulcers on her legs, which appeared for the first time at 8 years of age. Apart from recurrent lower respiratory tract infections and chronic otitis media, her personal history was unremarkable. Her parents were second‐degree relatives. The family history showed no similar disease or mental retardation. Physical examination revealed that the patient had an unusual facial appearance, with a high‐arched palate; she had multiple tooth caries (Fig. 1). Figure 1 Facial appearance of the patient There was edema and induration on both legs; extensive polygonal ulcers with elevated borders were noted. All lesions were 2–4 mm deep with vertical margins and a necrotic base. The surrounding skin was atrophic, and depigmented cicatricial lesions were detected (Fig. 2). She had crops of erythematous lesions and telangiectasias over the face, shoulders, arms, and extremities. She also showed photosensitivity, palmar hyperkeratosis, verrucous papules and plaques on the dorsal aspects of both feet consistent with lymphedematous changes, pes planus deformity, and hyperextensible joints. There was a scleroatrophic appearance and flexion contracture of the little fingers on both hands. Her abdomen was relatively protuberant and she had splenomegaly. Laboratory analysis revealed an elevated erythrocyte sedimentation rate, hypergammaglobulinemia, and iron deficiency anemia. A large amount of hydroxyproline was detected after hydrolysis of a 24‐h urine specimen (205 mg/day). Her plasma manganese level was 1.94 mg/dL (normal) and her vitamin C level was 1.4 mg/dL (below normal). Skin biopsies showed nonspecific inflammatory changes. Topical silver sulfadiazine and oral vitamin C (3 g/day) treatment was started. 2 Ulcers and depigmented cicatricial lesions on the legs

show abstract

Angiopathic pathogenesis of clinical manifestations in prolidase deficiency

Cited by 9 publications

References 0 publications

Prolidase deficiency: case reports of two Argentinian brothers

Prolidase deficiency: case reports of two Argentinian brothers

Extracellular matrix and HIF‐1 signaling: The role of prolidase

Prolidase deficiency

Contact Info

Product

Resources

About