RESUMO
Mutations in the early growth response 2 (EGR2) gene are associated with some forms of Charcot--Marie--Tooth disease (CMT) and other demyelinating neuropathies. These mutations modify the EGR2 binding to specific DNA sequences suggesting a role in the transcriptional control of myelination-specific genes. Here we show that the D355V mutation, associated with a CMT case combining axonal and demyelinating abnormalities, reduces three times the affinity of EGR2 to its consensus sequence and ten times its affinity to a sequence in the human Cx32 promoter. These findings could indicate that this EGR2 mutation leads to the development of CMT1 through the transcriptional deregulation of Cx32 gene.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Conexinas/genética , Proteínas de Ligação a DNA/metabolismo , Mutação Puntual , Regiões Promotoras Genéticas/fisiologia , Fatores de Transcrição/metabolismo , Adolescente , Ligação Competitiva/fisiologia , Doença de Charcot-Marie-Tooth/metabolismo , Criança , Proteína 2 de Resposta de Crescimento Precoce , Feminino , Expressão Gênica/fisiologia , Humanos , Bainha de Mielina/fisiologia , Transcrição Gênica/fisiologia , Proteína beta-1 de Junções ComunicantesRESUMO
Hereditary motor and sensory neuropathies (HMSN) comprises a wide clinical spectrum of related disorders with defects in peripheral nerve myelination. Charcot-Marie-Tooth type 1 (CMT1) is the most common form and is usually a mild disease with onset in the first or second decade; however there is a interfamilial and intrafamilial clinical variation, ranging from asymptomatic expression to severe muscular weakness and atrophy. Recently point mutations in the early growth response 2 gene (EGR2/Krox-20) have been associated with hereditary myelinopathies. We investigated for mutations at the EGR2 gene a patient with severe CMT1 phenotype. Direct sequencing of EGR2 gene showed a heterozygous A T transversion at nucleotide 1064 that predicts an Asp305Val substitution within the first zinc-finger domain. The finding of a novel EGR2 mutation associated with a different phenotype confirms that peripheral neuropathies represent a continuum spectrum of related disorders due to an underlying defect in myelination.