RESUMO
The most devastating complications of tuberous sclerosis complex affect the central nervous system and include epilepsy, mental retardation, autism, and glial tumors. Mutations in one of two genes, TSC1 and TSC2, result in a similar disease phenotype by disrupting the normal interaction of their protein products, hamartin and tuberin, which form a functional signaling complex. Disruption of these genes in the brain results in abnormal cellular differentiation, migration, and proliferation, giving rise to characteristic brain lesions called cortical tubers. Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and how disruption of their expression gives rise to the variety of clinical features that characterize tuberous sclerosis complex. In the future, these animals will be invaluable preclinical models for the development of highly specific and efficacious treatments for children affected with tuberous sclerosis complex.
Assuntos
Modelos Animais de Doenças , Proteínas/genética , Proteínas Repressoras/genética , Esclerose Tuberosa/fisiopatologia , Esclerose Tuberosa/veterinária , Animais , Criança , Genes Supressores de Tumor , Humanos , Camundongos , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/patologia , Proteínas/farmacologia , Proteínas Repressoras/farmacologia , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de TumorRESUMO
The canine tuberous sclerosis 2 (TSC2) gene has been mapped to canine chromosome 6 using a canine whole genome radiation hybrid panel. There is close linkage between canine TSC2 and the polycystic kidney disease 1 gene (PKD1), as has been observed in humans and other mammalian species. The gene responsible for the human juvenile form of neuronal ceroid lipofuscinosis (CLN3), maps close to TSC2 and PKD1 in humans, and is also syntenic in the dog. We further demonstrate linkage to a group of polymorphic markers assigned to canine chromosome 6 (CFA6).
Assuntos
Cromossomos , Doenças do Cão/genética , Genes Supressores de Tumor , Ligação Genética , Glicoproteínas de Membrana , Chaperonas Moleculares , Rim Policístico Autossômico Dominante/veterinária , Proteínas/genética , Proteínas Repressoras/genética , Esclerose Tuberosa/veterinária , Animais , Mapeamento Cromossômico/veterinária , Cães , Genótipo , Humanos , Lipofuscinoses Ceroides Neuronais/genética , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP , Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de TumorRESUMO
Tuberous sclerosis (TSC) is an autosomal dominant syndrome that is linked to two genetic loci: TSC1 (9q34) and TSC2 (16p13). Brain manifestations such as cortical tubers and subependymal hamartoma/giant cell astrocytomas are major causes of TSC-related morbidity. In this study, we describe the central nervous system involvement in a unique rodent model of tuberous sclerosis. The Eker rat carries a spontaneous germline mutation of the TSC2 gene and is predisposed to multiple neoplasia. In a series of 45 adult Eker carriers (TSC2 +/-), three types of focal intracranial lesions were found, of which the subependymal and subcortical hamartomas were most prevalent (65%). There exist remarkable phenotypic similarities between the Eker rat and human subependymal lesions. Our study indicates that the predominant cellular phenotype of the subependymal hamartomas is astroglial and suggests that the neuronal contribution within these lesions is, in part, the result of pre-existing myelinated axons. The hamartomas did not show evidence of loss of the wild-type TSC2 allele; it remains to be determined whether TSC2 inactivation is necessary for their pathogenesis. This genetically-defined rodent model may be useful in elucidating the molecular and developmental basis of the subependymal giant cell astrocytoma in humans.