Forma familiar de la enfermedad de Creutzfeldt-Jakob: marcadores genéticos en 4 familias chilenas / Genetic markers in four Chilean families with familial Creutzfeldt-Jakob disease

Background: Creutzfeldt-Jakob disease (CJD) is a form of transmissible spongiform encephalopathy, in which a prion protein (PrP Sc) accumulates in the brain of affected individuals. Chile has a prevalence of CJD that is more than twice than in the rest of the world and has the highest rate of familial forms. These later forms are associated with the heterozygocity of codon 200 of PrP protein gene. Aim: To search susceptibility genetic markers of CJD in members of families affected by CJD. Material and methods: A blood sample was obtained from 50 individuals pertaining to four families affected by CJD. DNA from peripheral mononuclear cells was amplified by polymerase chain reaction and sequenced for the gene that codifies PrP protein. Results: In family A, 21 of 23 members were homozygotes for codon 129 (Met/Met) and eight were simultaneously heterozygotes for codon 200 (Glu/Lys). In family B, six of nine members were homozygotes for codon 129, five were heterozygotes for codon 200 and four had both mutations. In family C, the four analyzed subjects were homozygotes for codon 129 and two were simultaneously heterozygotes for codon 200. In family D, nine of 14 members were homozygotes for codon 129 and two were simultaneously homozygotes for codon 200. No family had polymorphisms for codon 219. Conclusions: Thirty two percent of analyzed subjects were homozygotes for codon 129 and heterozygotes for codon 200, condition that defines the genetic susceptibility to acquire CJD. The dominant tendency of these genotypes could explain the higher incidence of CJF in Chile.

Insights into the physiological function of cellular prion protein

Prions have been extensively studied since they represent a new class of infectious agents in which a protein, PrPsc (prion scrapie), appears to be the sole component of the infectious particle. They are responsible for transmissible spongiform encephalopathies, which affect both humans and animals. The mechanism of disease propagation is well understood and involves the interaction of PrPsc with its cellular isoform (PrPc) and subsequently abnormal structural conversion of the latter. PrPc is a glycoprotein anchored on the cell surface by a glycosylphosphatidylinositol moiety and expressed in most cell types but mainly in neurons. Prion diseases have been associated with the accumulation of the abnormally folded protein and its neurotoxic effects; however, it is not known if PrPc loss of function is an important component. New efforts are addressing this question and trying to characterize the physiological function of PrPc. At least four different mouse strains in which the PrP gene was ablated were generated and the results regarding their phenotype are controversial. Localization of PrPc on the cell membrane makes it a potential candidate for a ligand uptake, cell adhesion and recognition molecule or a membrane signaling molecule. Recent data have shown a potential role for PrPc in the metabolism of copper and moreover that this metal stimulates PrPc endocytosis. Our group has recently demonstrated that PrPc is a high affinity laminin ligand and that this interaction mediates neuronal cell adhesion and neurite extension and maintenance. Moreover, PrPc-caveolin-1 dependent coupling seems to trigger the tyrosine kinase Fyn activation. These data provide the first evidence for PrPc involvement in signal transduction