Fatal Familial Insomnia and Familial Creutzfeldt-Jakob Disease: Disease Phenotype Determined by a DNA Polymorphism

TLDR

Fatal familial insomnia and a subtype of familial Creutzfeldt‑Jakob disease are distinct clinical and pathological entities that share the same Asn178 mutation in the prion protein gene. The study investigated whether a second genetic factor modifies the phenotypic expression of the Asn178 mutation. The diseases segregated with different genotypes defined by the Asn178 mutation and the methionine‑valine polymorphism at codon 129. In all affected members, the Met129‑Asn178 allele was associated with FFI, whereas the Val129‑Asn178 allele was associated with familial CJD, demonstrating that a common polymorphism determines distinct disease phenotypes from a single mutation.

Abstract

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD), two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asn 178 ) of the prion protein gene. The possibility that a second genetic component modified the phenotypic expression of the Asn 178 mutation was investigated. FFI and the familial CJD subtype segregated with different genotypes determined by the Asn 178 mutation and the methionine-valine polymorphism at codon 129. The Met 129 , Asn 178 allele segregated with FFI in all 15 affected members of five kindreds whereas the Val 129 , Asn 178 allele segregated with the familial CJD subtype in all 15 affected members of six kindreds. Thus, two distinct disease phenotypes linked to a single pathogenic mutation can be determined by a common polymorphism.