NR AWLN
AU Pacheco,P.; Orge,L.; Head,M.; Loureiro,P.; Silva,C.; Ironside,J.; Galo,A.; Coito,G.; Ventura,C.; Silva Dias,M.
TI Novel prion disease mutation R136S has an incomplete penetrance dependent upon codon 129 trans allele
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions GEN-22
PT Konferenz-Poster
AB A female patient diagnosed with familial early onset dementia, with two previously deceased (age 46 and 47 years) male siblings with the same neurodegenerative disease, started at age 52 with psychiatric symptoms, generalised myoclonus, Parkinsonic symptoms and progressive dementia. The EEG was lentified, MRI scan results were normal and CSF 14-3-3 was negative. The disease had 4 years of evolution. Genetic analysis of the PRNP gene revealed that the patient was homozygous for a novel mutation R136S linked to methionine at codon 129. R136S consists in a drastic aminoacid substitution in a conserved region of the gene. We didn't found this mutation in 340 unrelated PRNP alleles, thus concluding that it is not a polymorphism. Brain pathology studies on cerebral cortex and cerebellum, revealed little spongiform changes, but a very extensive formation of multicentric large amyloid plaques like in Gerstmann-Sträussler-Scheinker disease. The plaques labeled strongly with prion protein (PrP) antibodies 12F10 and 3F4, revealing massive PrP aggregation and deposition. The plaques showed the predominant involvement of cortical layers 3, 4 and 5 in the cerebral cortex, and the predominant involvement of the molecular layer in the cerebellar cortex. PrP proteinase K resistant western-blot analysis, revealed a distinct pattern with two low molecular weight bands of 5kDa and 8kDa. The patient's mother (age 93), half sister (age 87), daughter and son, were genetically analysed for the PRNP gene: both the mother and half sister were heterozygous for R136S and heterozygous at codon 129, but didn't develop this disease; the father's genotype was inferred as a carrier of the R136S (died age 80 without dementia). So, heterozygous for the R136S and for CD129 polymorphism, don't develop the disease. The disease caused by R136S in the PRNP gene is not transmitted as an autosomic dominant trait as expected. R136S has an incomplete penetrance dependent upon CD129 trans allele. The presence of a normal prion protein with Valine C at position 129 prevents the expression of the disease. The induction of the structural conversion of normal PrP SC into abnormal PrP seems to depend on the "proteic compatibility" between the abnormal and the normal prion coexisting in the cell. The "compatibility" depends on the aminoacid at position 129 that can be either Methionin or Valine, and only molecules with the same aminoacid at position 129 are compatible.
AD P. Pacheco, P. Loureiro, C. Silva: Centro de Genética Humana, Instituto Nacional de Saúde, Lisboa, Portugal; L. Orge, A. Galo: Laboratório Nacional de Investigação Veterinária, Lisboa, Portugal; M. Head, J. Ironside: National CJD Surveillance Unit, University of Edimburgh, Edimburgh, UK; G. Coito, C. Ventura: Hospital de Grândola, Grândola, Portugal; M. Silva Dias: Serviço de Neurologia, Hospital de Setúbal, Setúbal, Portugal. E-mail: paula.pacheco@insa.min-saude.pt
SP englisch
PO Italien