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Scrapie is a transmissible degenerative disease of the central nervous system occurring naturally in sheep. It belongs to the group of prion diseases also affecting man in which an abnormal isoform of the host-encoded prion protein (PrP) accumulating in the brain is responsible for neuronal death. Three main polymorphisms have been described in the sheep PrP gene, at positions 136, 154 and 171. A strong association between susceptibility/resistance to natural scrapie and a dimorphism at codon 136 of the ovine PrP gene has been reported in several breeds, including Romanov. This dimorphism, however, is not found in all scrapie-affected breeds. We have compared the PrP genotypes of Lacaune sheep obtained from enzootically affected flocks with those of apparently healthy sheep. A third variant at codon 171 was also evidenced. The results were compared with those obtained in a single experimental Romanov flock orally challenged with nematode parasites in which scrapie suddenly appeared and killed 80% of the sheep. We present evidence that, even in different epizootological circumstances, the major genetic factor controlling the susceptibility/resistance to natural scrapie in sheep, is represented by codon 171 genotype of the PrP gene. We also suggest that a modification of the allelic effects of codon 136 can occur in heavily infected animals.

Scrapie is a transmissible degenerative disease of the central nervous system occurring naturally in sheep and goats. An abnormal protease-resistant form of the host-encoded prion protein (PrP) accumulates in the brains of affected animals. As Sip, a gene controlling the incubation period of experimental and natural scrapie, is linked to the single-copy sheep PrP gene, we sought PrP coding sequence polymorphisms in flocks from the Romanov and Ile-de-France breeds endemically affected with natural scrapie. DNA samples from 153 sheep, including 29 natural scrapie cases, were screened by using polymerase chain reactions and denaturing gradient gel electrophoresis. Four predicted amino acid substitutions were found in the center of the PrP coding region: 112 Met--Thr, 136 Ala--Val, 154 Arg--His, and 171 Gln--Arg. These substitutions appeared mutually exclusive, defining five coding alleles. The 136Val allele, substituting a highly conserved Ala residue, in a homozygous or heterozygous state correlated with susceptibility to natural scrapie (chi 2 = 64.33, P0.001). This correlation indicates that the 136 Val allele may modulate development of the disease, implying a pivotal role for PrP molecules in natural scrapie, as has been observed for experimental scrapie and human prion diseases.

We screened 16 cases of sporadic Creutzfeldt-Jakob disease (CJD) and 28 healthy control subjects to detect possible polymorphisms in their prion protein gene (PRNP). The molecular analysis of the PRNP coding sequence was performed using denaturing gradient gel electrophoresis of polymerase chain reaction products and direct sequencing. We identified (1) a silent mutation at codon 177 in a healthy individual, (2) a codon 200 glutamate-to-lysine substitution in a 48-year-old CJD-affected Libyan Jew, and (3) a G-to-A point substitution at codon 210, leading a valine-to-isoleucine change, in a 63-year-old French CJD patient. This new mutation occurs in a highly conserved part of the PRNP coding sequence, close to the known CJD-associated codon 200 mutation, and might be linked to a symptomatologic and neuropathologic pattern of typical sporadic CJD. This mutation was also present in a sister of the patient who died at the age of 67 without neurologic symptomatology.