RESUMO
Machado-Joseph disease (MJD) is an autosomal dominantly inherited neurodegenerative disorder characterized by varying age of onset and pronounced phenotypic heterogeneity. The clinical core features include gait ataxia, external ophthalmoplegia, nystagmus, and bulging eyes. Recently, Kawagushi et al. (1994) cloned the MJD1 gene on chromosome 14 and MJD turned out to be the fifth neurodegenerative disease caused by an unstable CAG repeat expansion. We have studied two large Danish families and one Norwegian family with MJD. Three features not previously associated with MJD are reported: dementia, generalized muscle and joint pain, and in one case neuropathological examination revealed atrophy of the inferior olives. We found a significant inverse correlation between age of onset and the length of the CAG repeat expansion, and anticipation is described through four succeeding generations. Instability of the CAG repeat expansion was most pronounced at paternal transmission.
Assuntos
Doença de Machado-Joseph/diagnóstico , Adulto , Idoso , Ataxina-3 , Demência/genética , Feminino , Humanos , Doença de Machado-Joseph/genética , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares , Linhagem , Fenótipo , Proteínas Repressoras , Países Escandinavos e Nórdicos , Repetições de TrinucleotídeosRESUMO
The Huntington disease gone encodes the protein huntington, which is widely expressed during embryonic development and in mature tissues. In order to elucidate the physiological function of huntington, which so far is unknown, we intend to study the effect of antisense down-regulated huntington expression. We have found an inhibiting effect of a phosphorothioated oligodeoxynucleotide (PS-ODN) added to the culture medium of embryonic teratocarcinoma cells (NT2) and postmitotic neurons (NT2N neurons) differentiated from the NT2 cells. Specific inhibition of expression of endogenous huntington was achieved in NT2N neurons in the concentration range of 1-5 microM PS-ODN, whereas no inhibition was obtained in NT2 cells. We describe in detail the selection of the target sequence for the antisense oligo and the uptake, intracellular distribution, and stability of the antisense PS-ODN in the two cell types. Antisense down-regulation of huntington in this model of human neurons represents a suitable approach to study its normal function.