Calendário de Defesas e Seminários

Data: Segunda-feira, 11 de Novembro de 2019 (10:30 - 23:59)

Molecular characterization of Genodermatosis: functional and phylogenetics analysis in Neurofibromatosis type 1 and Tuberous Sclerosis Complex

Orientadora: Dra. Patricia Ashton-Prolla

Coorientadora: Dra. Clévia Rosset

Banca Examinadora: Dra. Úrsula da Silveiar Matte (Dep. de  Genética – PPGBM) e Dra. Patricia Luciana da Costa Lopez (PPGGastro – HCPA - GPPG)

11 de novembro de 2019 (segunda-feira)


Anfiteatro do Departamento de Genética, Prédio 43312, Campus do Vale/UFRGS


Genodermatoses are a large group of diseases caused by spontaneous or hereditary mutations, with cutaneous manifestations and frequent involvement of other organs, especially the central nervous system. Among the most common Genodermatoses are Neurofibromatosis type 1 (NF1 - OMIM #162200), which affects 1 in 3,000 individuals and Tuberous Sclerosis (TSC - OMIM #191100), which occurs at a frequency of 1 in 6,000 live births.  NF1 is characterized by benign cutaneous neurofibromas and plexiform neurofibromas, as well as pigmentary abnormalities such as café au lait spots on the skin, iris Lisch nodules, and axillary and inguinal freckling. Learning disabilities and orthopedic problems are other symptoms that occur in up to 50% of patients. Less common but more serious manifestations include optic nerve and central nervous system  gliomas, scoliosis, tibial dysplasia, and vasculopathy. The number of possible complications and the phenotypic pattern of the disease vary greatly between individuals. NF1 is an autosomal dominant disorder with complete penetrance and around 50% of cases are caused by de novo mutations. At least 3197 different mutations in NF1 gene have been identified. Large deletions, involving variable regions of the gene with or without involvement of other genes on the long arm of chromosome 17, are present in 5-10% of patients and are called microdeletions. The most frequent microdeletions are approximately 1.5 Mb, involving the entire NF1 gene and 13 other flanking genes, most of which have currently no known function. Patients with microdeletions tend to have a different phenotype when compared to those with small NF1sequence alterations, including appearance of neurofibroma at an earlier age, lower average IQ, dysmorphic facial features, and a high risk of developing malignant sheath tumors. Clinical variability of NF1 is likely to result from a combination of genetic, environmental and stochastic factors. Such complexity, together with the diversity of mutations that occur in this disease, render establishment of genotype-phenotype correlations difficult. Only a few studies have investigated such correlations in NF1 to date, and additional data are needed to verify the usefulness of genetic testing in phenotype prediction.

Tuberous sclerosis complex (TSC) is an autosomal dominant and multisystem disorder that affects children and adults, often causing neurological symptoms including epilepsy, mental retardation and autism. Like NF1, it is a disease with variable phenotypic expression, with the potential to affect virtually any organ in the body. Common clinical manifestations of TSCinclude abnormalities of skin and mucous membranes, epilepsy (affects up to 90% of patients) and cognitive deficiency (observed in about 70% of patients). The three main intracranial lesions associated with the disease are cortical tubercles, subependymal nodules, and subependymal giant cell astrocytomas. In addition, patients may develop angiomyolipomas and lymphangioleiomyomatosis. TSC is caused by heterozygous mutations that inactivate TSC1 (OMIM #605284) or TSC2 (OMIM #191092). The two proteins encoded by these genes form the TSC complex, which negatively regulates mTORC1 complex signaling. Considering that mTORC1 is a key inhibitor of autophagy through direct ULK1 phosphorylation, TSC can provide a unique opportunity to investigate the implications of autophagy dysregulation in a human diseases. In this sense, our three main objectives are: (1) an in silico approach to establish genotype-phenotype correlations of microdeletions in NF1 through phylogenetic studies; (2) an in vitro approach to assess autophagy in Tuberous Sclerosis Complex; (3) a study to evaluate the presence of cryptic variants that may affect RNA processing sites in patients with NF1 and TSC without identifiable coding region variants or patients with variants ofUncertainlySignificance(VUS). This study intends to contribute to the understanding of the molecular genetics of these diseases, as well as to the definition of genotype-phenotype correlations and evaluation of novel treatment opportunities in these disorders.

Local  Anfiteatro do Departamento de Genética, Prédio 43312, Campus do Vale/UFRGS
Contato: PPGBM - Av. Bento Gonçalves, 9500 - Prédio 43312 M - Telefone: (51)3308-6722 / E-mail:
por Tamara Moch