Estudo de mutações no gene SEPN1 em pacientes brasileiros portadores de miopatias e distrofias musculares congênitas

Abstract

Introduction: different kinds of myopathy are related to the selenoprotein N gene, among which: congenital muscular dystrophy with rigid spine (RSMD) multiminicore myopathy (MmD), desminopathy with Mallory body and congenital fiber-type disproportion myopathy (CFTD). Until the present moment there aren´t national studies that evaluated mutations in the gene SEPN1 in brazilian patients with myopathy related to selenoprotein N. This study is a dissertation and will be presented in the form of two papers: the first, a literature review of myopathies related to selenoprotein N and the second shows the results of the study of SEPN1 gene in Brazilian patients with such condictions. Objective: to evaluate the presence of mutations in the SEPN1 gene in Brazilian patients with myophathies related to selenoprotein N and to correlate the clinical, histopathological and genetic findings. Methodology: patients with myopathies related to SEPN1 gene were submited to: clinical evaluation, measurement of creatinephosphokinase (CPK), electromyography (ENMG) and muscle biopsy with histochemistry study because of diagnosis. We conducted a research protocol, through the medical record and clinical data of patients. We reviewed the muscle histopathology of patients included in the research and molecular study of patients, some family members and normal controls, by technique of polymerase chain reaction (PCR) and sequencing of the gene SEPN1. Results: Were included eighteen patients from sixteen different families. This patients ten were classified with, seven patients were classified with MmD and one patient with CFTD. The molecular analysis revealed mutations in six families. Family 1: A patient with classic phenotype of MmD with compound heterozygous mutation (cG1010T/cT1384G). Family 2 and 3: Two patients unrelated with RSMD phenotype with insertion of a base out of phase in heterozygous (c713- 714insA). Família 4: One patient with CFTD showed insertion of 12 bases in phase (c316-317 Ins.12bp). Family 5: One patient with MmD prenatal form with arthrogryposis showed a missense mutation in heterozigose (cG583A) in which the complementar change was not identified. Family 6: Three affected siblings with myopathy and stiff neck which was identified one insertion in phase of three base pairs in heterozygous (c438-439ins3bp). Conclusion: Myopathies related to selenoprotein N have a wide clinical phenotype and histology. Among the six mutations found two (C713-714insA and cT1384G) had previously been described in the literature as pathogenic in patients with DMER and MmD. The others four changes were not found descriptions in the literature. The mutation cG1010T was found in compound heterozygous with the pathogenic mutation cT1384G in a patient with MmD, being considered due to theircharacteristics and absence in normal controls, a new pathogenic mutation. The mutation c438-439ins3bp, is a polymorphism because it was found homozygous in a parent asymptomatic and in 2% of normal controls.The other two mutations cG583A and c316-317Ins12bp require further studies for better elucidation as to its pathogenicity. The molecular analysis can help confirm the diagnosis, as well as genetic counseling of families