Creutzfeldt‐Jakob disease cosegregates with the codon 178^AsnPRNP mutation in families of European origin

Abstract

We recently discovered an amino acid-altering heterozygous mutation in codon 178 of the PRNP amyloid precursor gene in patients with familial Creutzfeldt-Jakob disease. This mutation is now shown to be associated with the occurrence of disease in 7 unrelated families of Western European origin, among which a total of 65 members are known to have died from Creutzfeldt-Jakob disease. The mutation was detected in each of 17 tested patients, including at least 1 affected member of each family, and in 16 of 36 of their first-degree relatives, but not in affected families with other mutations, patients with the nonfamilial form of the disease, or 83 healthy control individuals. Linkage analysis in two informative families yielded a lod score of 5.30, which, because no recombinants were found, strongly suggests that codon 178Asn is the actual disease mutation.

Swaledale sheep affected by natural scrapie differ significantly in PrP genotype frequencies from healthy sheep and those selected for reduced incidence of scrapie

“…Most, but not all, GSS families have a proline to leucine substitution at codon 102 (Hsaio et al, 1989(Hsaio et al, , 1991 and there are many different PrP mutations associated with familial CJD (Owen et al, 1990;Goldfarb et al, 1992). By analogy, different sheep breeds and flocks (sheep 'families') may also have different predominating PrP genotypes in their scrapie-affected members.…”

D178N, 129Val and N171S, 129Val Genotype in a Family with Creutzfeldt-Jakob Disease

“…The first-generation female of this family identified in figure 3 is thought to have been of mixed black and white ancestry, raising the possibility that this family may be related to one of the previously described families. Although the family history is incomplete, it is possible that the phenomenon of genetic anticipation, determined by the mean age at disease onset, is observed through subsequent generations (3rd generation -60 years old, 4th generation -58 years old, 5th generation -49 years old), which has been observed in several other families with genetically transmitted prion diseases [4,9,10] . A higher proportion of males are affected in this family (n = 6, ratio 2.0), which is similar to other reports [11] .…”

“…This point mutation is shared by FFI and CJD D178N, 129V [4] , but the two phenotypes differ in their polymorphism at codon 129 of the mutant allele. FFI contains the amino acid methionine (Met) at codon 129 of the mutant allele as opposed to gCJD, which contains valine (Val) at codon 129.…”

Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism.

“…Mutations at PRNP codons 102, 105, 117, 198, and 217 are associated with GSS subtypes (12,13), while a mutation at codon 200 is linked to one CJD subtype, CJD2m (14). A mutation at codon 178 that results in the replacement of aspartic acid by asparagine (Asp-178 --Asn) is shared by FFI and another CJD subtype, CJD178 (4,(15)(16)(17). In spite of the common mutation, these two diseases are phenotypically distinct since in CJD178 severe sleep impairment has not been reported and there is widespread spongiosis rather than selective thalamic atrophy.…”