The Prion Protein Gene Prnp

The human PRNP is located on the short arm of chromosome 20 and contains a short 5' exon, followed by a large intron and then a 3' exon, which encodes the entire 253 amino acids of the open reading frame of the precursor PrP.[1] Within the gene, three polymorphic regions—i.e., a single octapeptide deletion, M129V, and E219K—have been described, as well as a growing number of spontaneous or inherited mutations associated with the development of CJD.[2]

Investigations of sporadic CJD cases and people infected with CJD through the administration of human cadaveric pituitary gland hormones, such as growth hormone or gonadotropin, have revealed that the codon 129 M/V polymorphism influences susceptibility to disease as a consequence of both mutations within PRNP[3] and exposure to infectious material.[4] The major determinant of risk for iatrogenic and sporadic CJD seems to be homozygosity at codon 129.[5]

The same polymorphism can also determine the phenotype of disease as exemplified by the D178N PRNP mutation, which results in fatal familial insomnia (FFI) if M129 is present on the same allele, and in CJD if V129 is present on the same allele, with an additional correlation between codon 129 homozygosity and disease severity in both instances.

Variant CJD (vCJD), a new prion disease first recognized in 1996, is presumed to be caused by oral infection of humans with the bovine spongiform encephalopathy (BSE) agent. To date, approximately 140 cases have been diagnosed, principally in the United Kingdom, where the majority of BSE cases have occurred. All the cases investigated were codon 129 M/M homozygous, which indicates that either other genotypes are not susceptible, or their incubation periods are significantly longer. Experience with kuru, which—as far as we know—is the only other human prion disease acquired orally and was transmitted through ritualistic cannibalism among the Fore people of Papua New Guinea, supports the latter. In the later stages of the kuru epidemic, people carrying the most susceptible codon 129 M/M genotype had practically been depleted from the Fore survivors, and those who were heterozygous or carried the V/V genotype only developed the disease after extremely long incubation periods of 20

Determinations of the codon 129 genotype, as typically performed via oligonucleotide hybridization, or recently by a more simple and cost-effective polymerase chain reaction/restriction digestion assay,[7] have revealed approximately 50% heterozygosity, approximately 40% M/M homozygosity, and only 10% V/V homozygosity for healthy Caucasian populations.[7,4] In marked contrast, only around 8% of the Japanese population is heterozygous at codon 129.[8]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

Get My Free Ebook

Post a comment