Clinical-genetic-biochemical characterization in patients with porphyria cutanea tarda

• Grant number: 23/17551-1
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2024
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: João Bosco Pesquero
• Grantee: João Bosco Pesquero
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Mônica Ribeiro de Azevedo Vasconcellos ; Renata Ferreira Magalhães ; vitor manoel silva dos reis

Abstract

Porphyria Cutaneous Tarda (PCT) is a multifactorial disorder in heme synthesis, defined by reduced activity of the enzyme uroporphyrinogen decarboxylase (UROD) and subdivided into three clinically indistinguishable subtypes. PCT is characterized by non-inflammatory vesicobullous skin lesions that rupture and form scars or atrophic areas on the back of the hands, forearms, legs and feet, in addition to frontotemporal and upper malar hypertrichosis. Patients are at greater risk of secondary infections due to Hepatitis B and C and Human Immunodeficiency Virus, as well as a greater predisposition to hepatocellular carcinoma. The diagnosis is confirmed by increased levels of porphyrins in the urine. Type I, the most common, is a sporadic form related to liver dysfunction triggered by environmental factors, such as medications, alcohol, hormones, diet, stress, sun exposure and others. Type II presents, associated with environmental factors, heterozygous mutations in the UROD gene (1p34.1), responsible for the formation of the homonymous enzyme with autosomal dominant inheritance of low penetrance. Considering the higher incidence of type I PCT, we propose to carry out a clinical-genetic-biochemical characterization of PCT carriers to determine individuals at risk for this disease and prevent its onset. About 50% of PCT carriers carry mutations related to hemochromatosis, such as homozygosity for the C28Y mutation in the HFE gene (6p22.2). This gene transcribes the HFE protein, responsible for regulating the entry of iron into hepatocytes and enterocytes, and the presence of this mutation increases the risk of developing PCT by 60 times. Therefore, this work proposes to carry out a dermatological medical evaluation followed by complete sequencing of the UROD and HFE gene (by exome analysis), analysis of large deletions/insertions by the MLPA technique, evaluation of intronic variants by mRNA and UROD activity in plasma and in erythrocytes from patients and controls. Although PCT is a rare genetic disease, a better understanding of the genetic and biochemical bases of this disease will make it possible to detect individuals at risk for the disease and prevent its appearance using genetic counseling for patients and their families, as well as contributing to the development of diagnostic methods. and early and effective treatment. (AU)