NR ATPT
AU Chasseigneaux,S.; Peoc'h,K.; Haik,S.; De Marco,O.; Launay,J.M.; Lenne,M.; Brandel,J.P.; Laplanche,J.L.
TI V180I mutation of the prion gene associated to atypical PrPsc glycosylation
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Pathogenesis PATH-30
PT Konferenz-Poster
AB
Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). A V180I mutation in the prion protein gene was identified in a French patient with histopathologically confirmed prion disease. This rare mutation - seven patients described worldwide - is located in the vicinity of a N-glycosylation consensus site of PrP. Clinically, this form of prion disease was characterized by a long evolution, the absence of familial history and of cerebellar symptoms. Neuropathological examination revealed a severe spongiform changes and gliosis in the isocortex, the striatum, and the entorhinal cortex. Western blot analysis of the patient's brain tissue showed PK resistant PrP with a definite preponderance of the mono- and unglycosylated forms. However, PrPc appears normally glycosylated in the patient's brain. Cell culture experiments confirmed the apparently normal glycosylation of the mutant protein. Thus, it seems that biglycosylated PrPc, while well expressed into the CNS, cannot be converted into a PK-resistant isoform in case of V180I patient. Interestingly, MoPrP179I (murine PrP with Isoleucine at residue 179, murine counterpart of mutation) did not exhibit any resistance to PK when transfected into CHO cells even when incubated with very low protease concentration while MoPrP199K, chosen as control, still exhibited partial resistance with 20-fold higher PK concentration.
This description of the mutation in a Caucasian patient gives new insights into the mechanism of PrPc conversion underlying the putative role of the 180 residue of human PrP. Whether PrP180I is able to transmit the disease to rodents overexpressing PRNP remains to be determined and will add to the debate on the influence of PrP glycosylation on prion infectivity.
AD Stephanie Chasseigneaux, Katell Peoc'h, Jean-Marie Launay, Martine Lenne, Jean-Louis Laplanche, UPRES EA 3621, UFR des Sciences Pharmaceutiques et Biologique, Université Paris 5 et Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, Paris, France; Stephane Haïk, Inserm Equipe Avenir- Maladies Humaines Prions, IFR70, Neuropathologie, Hopital de La Salpetriere, Paris, France; Olivier De Marco, Service de Médecine Interne, Centre Hospitalier Départemental, La Roche-sur-Yon, France; Jean-Philippe Brandel, U360, Hôpital de La Pitié-Salpêtrière, Paris, France
SP englisch
PO Deutschland