RESUMO
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.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Substituição de Aminoácidos , Criança , Cromossomos Humanos Par 17 , Proteína 2 de Resposta de Crescimento Precoce , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , Dedos de Zinco/genéticaRESUMO
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.