Kuru, Susceptibility To

A number sign (#) is used with this entry because of evidence that kuru is an acquired form of prion disease, associated with variation in the PRNP gene (176640).

Description

Kuru, a fatal neurodegenerative condition, is a human prion disease that primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning ('transumption'). The incidence has fallen dramatically since the cessation of cannibalism in the 1950s (summary by Wadsworth et al., 2008).

Clinical Features

Collinge et al. (2006) identified 11 patients with kuru in Papua New Guinea who were all born before the cessation of cannibalism. The most likely incubation period in men ranged from 39 to 56 years. Most of the patients were homozygous at the PRNP 129 residue (M129V; 176640.0005). The findings indicated that kuru can have a very long incubation time, which may affect epidemiologic studies of other prion diseases.

Molecular Genetics

By PRNP genotyping of frozen blood samples from 92 patients with kuru, Cervenakova et al. (1998) found that homozygosity at codon 129 (M129V; 176640.0005), particularly for methionine, was associated with significantly earlier age at onset and a shorter duration of illness compared to heterozygosity at codon 129. However, other clinical characteristics were similar for all genotypes at codon 129. Cervenakova et al. (1998) noted that all cases of variant Creutzfeldt-Jakob disease (vCJD; see 123400), which is caused by oral ingestion of infected tissue, have been shown to be homozygous for met129. As kuru is the most appropriate transmissible prion disease for comparison to vCJD by virtue of its oral and/or mucocutaneous route of infection, the authors hypothesized that evolution of vCJD may be associated with genetic heterogeneity at PRNP codon 129.

Mead et al. (2009) identified a gly127-to-val (G127V; 176640.0028) SNP in inhabitants of the Eastern Highlands of Papua New Guinea. Genotyping of more than 3,000 individuals, including 709 who participated in cannibalistic mortuary feasts of whom 152 subsequently died of kuru, found that heterozygosity (127GV) for the G127V polymorphism conferred protection against kuru. The val127 variant was invariably linked to the met129 (176640.0005) polymorphism and was found exclusively in people from the Purosa Valley and neighboring villages, where kuru was prevalent. The frequency of the 127GV genotype was 0.08. Thirty-six of 48 patients with kuru who were younger than 20 years of age carried the 127GG/129MM or 127GG/129VV genotype compared to 36 of 125 elderly women who were resistant to kuru (p = 3.4 x 10(-8)) and 27 of 104 patients with kuru who were older than 20 years (p = 1.2. x 10(-8)), indicating that heterozygosity at these SNPs confers protection. In addition, the 127GV genotype was not found in any patients with kuru, suggesting that it may provide complete resistance to the disease. Approximately 50% of the 51 127V-containing chromosomes shared a common haplotype, indicating a common ancestor about 10 generations ago. The findings were consistent with selection pressure.

Population Genetics

Kuru is largely restricted to the Fore linguistic group of the Papua New Guinea Eastern Highlands and was transmitted during endocannibalistic feasts (Mead et al., 2003). Heterozygosity for a common polymorphism in the human prion protein gene confers relative resistance to prion diseases. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are, in marked contrast to younger unexposed Fore, predominantly PRNP 129 heterozygotes. Kuru imposed strong balancing selection on the Fore, essentially eliminating PRNP 129 homozygotes. Mead et al. (2003) cited evidence suggesting that cannibalism was widespread in many prehistoric populations and may have provided the setting for selection pressure as protection against prion disease. Worldwide PRNP haplotype diversity and coding allele frequencies suggest that strong balancing selection at this locus occurred during the evolution of modern humans.

Kreitman and Di Rienzo (2004) and Soldevila et al. (2005) suggested that the findings reported by Mead et al. (2003) were due to ascertainment bias and did not reflect balancing selection. In an analysis of 174 individuals worldwide genotyped for the PRNP 129 polymorphism, Soldevila et al. (2006) found no evidence for selective forces other than purifying selection. The findings disputed the hypothesis suggested by Mead et al. (2003).

Hardy et al. (2006) found significantly higher frequencies of the PRNP val129 allele in several Central and South American populations compared to the very low frequencies among East Asian populations from which they derived. The authors noted that cannibalism has been documented in the Americas, particularly among the Aztecs. The authors agreed with the hypothesis suggested by Mead et al. (2003) of selection pressure at the prion locus, and hypothesized that a devastating kuru-like epidemic may have occurred in the Americas, resulting in increased frequency of the val129 allele.

Pathogenesis

Reproduction of the disease clinically and histopathologically in chimpanzees injected with material from the brain of human cases (Gajdusek et al. (1966, 1967)) suggested that kuru is due to a 'slow virus.' Whether significant genetic factors are also involved remains uncertain. ('Scrapie' is a chronic neurologic disease of sheep in which involvement of a 'slow virus' has also been proposed; however, genetic factors may also be involved.) Bennett et al. (1959) had suggested that affected males were homozygous and affected females either homozygous or heterozygous for a single gene for kuru. However, many later studies clearly showed that kuru, scrapie, and other encephalopathies such as Creutzfeldt-Jakob disease (CJD; 123400) are not caused by 'slow virus' infection but arise through horizontal infection and accumulation of aberrant prion protein (176640) in the brains of affected individuals (e.g., Kingsbury, 1990). The cerebellar prion protein is converted into an aberrant isoform by posttranslational modification. For review, see Prusiner and Hsaio (1994).

Animal Model

Wadsworth et al. (2008) found that the conformation of pathogenic PrP(Sc) fragments isolated from the brains of 3 individuals with kuru were similar to those seen in classic sporadic CJD. Kuru-inoculated transgenic mice carrying human homozygous PRNP val129 showed transmission rates similar to those of classic CJD, not variant CJD. All 3 kuru isolates resulted in 100% rates of prion infection with clinical disease and a mean incubation time of about 200 days. Kuru-inoculated and sporadic CJD-inoculated transgenic mice showed similar neuropathologic changes that were distinct from variant CJD. The findings were consistent with the theory that kuru originated from chance consumption of an individual with sporadic CJD.

In contrast to the findings of Wadsworth et al. (2008), Manuelidis et al. (2009) concluded that the kuru infectious agent is a unique geographic isolate distinct from CJD and scrapie. Manuelidis et al. (2009) transmitted primate kuru to mice expressing normal and increased levels of the murine prion protein. Features of mice transmitted with sporadic CJD, variant CJD (BSE), and scrapie were clearly different from the features of mice transmitted with kuru with respect to incubation time, brain neuropathology, lymphoreticular involvement, and clinical signs. Differences between the pathogenic agents were also observed in in vitro studies using monotypic GT1 cells. The incubation time of kuru was shortened significantly in transgenic mice with increased levels of the murine prion protein, suggesting that host variability can influence susceptibility and virulence, and that the kuru infectious agent can adapt rapidly.