Host genetic factors play a major role in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Polymorphisms in the prion protein gene (PRNP) modulate susceptibility as well as phenotypic expression in both human and animal TSEs. Moreover, familial forms of TSEs in humans are associated to specific PRNP mutations. Despite the strong role of PRNP, additional genetic loci have been postulated since PRNP variability do not fully explain disease susceptibility and incubation times. Genetic variability in Apo E, ADAM 10, Doppel, LamR1, PLG, Hsp70 have been previously examined in Creutzfeldt-Jacob disease (CJD) with inconclusive findings. Calpain, a cysteine protease, has been implicated in the pathogenesis of different neurodegenerative including prion disease. We investigated whether variability in the calpain gene may contribute to susceptibility or phenotypic expression of sporadic CJD. We analyzed 5 single nucleotide polymorphisms within the calpain 1 gene as potential markers in linkage disequilibrium with a functional polymorphism. 200 subjects with confirmed sporadic CJD were studied. The polymorphisms located either in one “EF hand” domain or in the proteolytic domain, were identified by dHPLC and/or sequencing analyses. 3 polymorphisms (rs 17880882, rs 11227153, rs 542380) did not show any significant difference in the genotype or allele frequencies between CJD subjects and healthy controls, whereas the remaining two (rs 2277307 and rs 11227146), which were found to be in linkage disequilibrium, demonstrated a different distribution in sporadic CJD carrying VV at codon 129. Our results seem to exclude a major role of the calpain 1 gene in modulating susceptibility or phenotypic expression of sporadic CJD. A potential subtype-specific role of calpain 1 gene variants should be investigated further in larger sample groups.

Variations at the Calpain 1 gene locus in sporadic Creutzfeldt-Jakob disease

CESCATTI, MAURA;CAPELLARI, SABINA;PARCHI, PIERO
2005

Abstract

Host genetic factors play a major role in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Polymorphisms in the prion protein gene (PRNP) modulate susceptibility as well as phenotypic expression in both human and animal TSEs. Moreover, familial forms of TSEs in humans are associated to specific PRNP mutations. Despite the strong role of PRNP, additional genetic loci have been postulated since PRNP variability do not fully explain disease susceptibility and incubation times. Genetic variability in Apo E, ADAM 10, Doppel, LamR1, PLG, Hsp70 have been previously examined in Creutzfeldt-Jacob disease (CJD) with inconclusive findings. Calpain, a cysteine protease, has been implicated in the pathogenesis of different neurodegenerative including prion disease. We investigated whether variability in the calpain gene may contribute to susceptibility or phenotypic expression of sporadic CJD. We analyzed 5 single nucleotide polymorphisms within the calpain 1 gene as potential markers in linkage disequilibrium with a functional polymorphism. 200 subjects with confirmed sporadic CJD were studied. The polymorphisms located either in one “EF hand” domain or in the proteolytic domain, were identified by dHPLC and/or sequencing analyses. 3 polymorphisms (rs 17880882, rs 11227153, rs 542380) did not show any significant difference in the genotype or allele frequencies between CJD subjects and healthy controls, whereas the remaining two (rs 2277307 and rs 11227146), which were found to be in linkage disequilibrium, demonstrated a different distribution in sporadic CJD carrying VV at codon 129. Our results seem to exclude a major role of the calpain 1 gene in modulating susceptibility or phenotypic expression of sporadic CJD. A potential subtype-specific role of calpain 1 gene variants should be investigated further in larger sample groups.
Prion 2005. Between fundamentals and society's needs
234
234
M. Cescatti; S. Capellari; P. Gambetti; P. Parchi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/27184
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