Diagnostico molecular e aspectos clínicos de brasileiros com mutação do gene Hnf1b: analise do recrutamento de pacientes por presença de cistos renais e hiperglicemia

• Autor(a) principal: Dotto, Renata Pires [UNIFESP]
• Data de Publicação: 2018
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=6319280; https://repositorio.unifesp.br/handle/11600/52226
• topic: Biologia molecular; Diabetes mellitus; Molecular biology

INTRODUCTION: Diabetes mellitus (DM) is a heterogeneous group of diseases that has the characteristic of chronic hyperglycemia. In most of these diseases there are the interaction of genetic and environmental factors. However, there are several monogenic forms of DM, especially the Maturity Onset Diabetes of the Young (MODY). There are at least 14 genes that are associated with this type of DM, with predominance of secondary forms of mutations in HNF1A and GCK genes. HNF1B mutations gene are associated with MODY. The secondary syndrome relative of mutation in this gene, initially denominated "Syndrome of Cysts Renal and Diabetes" results in a very heterogenous phenotype, with manifestations in several organs. In the last years, there are proposals to optimize the recruitment of patients with mutations in this gene, although by phenotypes selection related or for elaboration of risk scores. There are few Brazilian studies that investigated mutations in the HNF1B gene and the clinical consequence. OBJECTIVE: The aims of our study was: to analyse genetic diagnosis and to describe clinical characteristics of Brazilians patients with mutation in the HNF1B gene. To investigate the positivity rate of the test using two strategies: clinical suspicion for MODY and negative for mutations in the GCK and HNF1A genes and through the selection of patients for the presence of renal cysts and hyperglycemia. MATERIAL AND METHODS: In an article we selected 32 patients due to clinical suspicion for MODY and negative for mutations in the GCK and HNF1A genes, independent of the phenotype. In another article, we selected 29 patients with clinical suspicion of HNF1B-MODY who presented renal cysts and hyperglycemia. For these analyzes we use the MLPA and Sanger Sequencing techniques. Clinical data were taken by medical records. RESULTS: In the study who the patients were selected by the negativity of mutations in the GCK and HNF1A genes, we found a positive case (3% positivity in the cohort). The patient presented heterozygous whole gene in HNF1B, presenting the following clinical characteristics: DM, diabetic retinopathy, renal failure, hypomagnesemia and alterations in liver enzyme tests. In the other article who selected patients by renal cysts and hyperglycemia we found two patients with variants in this gene (7% positivity in the cohort). A case with the mutation p.Pro328Leufs * 48 (c.983delC) and the following clinical data: renal cysts, DM, hypomagnesaemia, hypertension and hypertrophic cardiomyopathy. The other patient presented heterozygous whole gene in HNF1B, presenting the following clinical features: renal cysts, DM, hypomagnesaemia, agenesis of body and tall of pancreas, hypertension, dyslipidemia, exocrine pancreatic insufficiency, subclinical hypothyroidism. After confirmed this patient, we performed the tests in the available relatives and confirmed the same mutation in another three subjects, whose phenotype included renal cysts and agenesis of pancreas in all patients and one with hypomagnesemia and bicornuate uterus. CONCLUSION: We performed the genetic diagnosis and described the clinical characteristics of Brazilian patients with mutation in the HNF1B gene, whose the phenotype was heterogeneous. The positivity rate of Brazilian patients for mutation in the HNF1B gene recruited for the presence of renal cysts and hyperglycemia was 7%.