A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure

A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure


Simon Mead, M.R.C.P., Jerome Whitfield, M.A., Mark Poulter, B.Sc., Paresh Shah, Ph.D., James Uphill, B.Sc., Tracy Campbell, B.Sc., Huda Al-Dujaily, B.Sc., Holger Hummerich, Ph.D., Jon Beck, B.Sc., Charles A. Mein, Ph.D., Claudio Verzilli, Ph.D., John Whittaker, Ph.D., Michael P. Alpers, F.R.S., and John Collinge, F.R.S.


ABSTRACT

Background Kuru is a devastating epidemic prion disease that affected a highly restricted geographic area of the Papua New Guinea highlands; at its peak, it predominantly affected adult women and children of both sexes. Its incidence has steadily declined since the cessation of its route of transmission, endocannibalism.

Methods We performed genetic and selected clinical and genealogic assessments of more than 3000 persons from Eastern Highland populations, including 709 who participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru.

Results Persons who were exposed to kuru and survived the epidemic in Papua New Guinea are predominantly heterozygotes at the known resistance factor at codon 129 of the prion protein gene (PRNP). We now report a novel PRNP variant — G127V — that was found exclusively in people who lived in the region in which kuru was prevalent and that was present in half of the otherwise susceptible women from the region of highest exposure who were homozygous for methionine at PRNP codon 129. Although this allele is common in the area with the highest incidence of kuru, it is not found in patients with kuru and in unexposed population groups worldwide. Genealogic analysis reveals a significantly lower incidence of kuru in pedigrees that harbor the protective allele than in geographically matched control families.

Conclusions The 127V polymorphism is an acquired prion disease resistance factor selected during the kuru epidemic, rather than a pathogenic mutation that could have triggered the kuru epidemic. Variants at codons 127 and 129 of PRNP demonstrate the population genetic response to an epidemic of prion disease and represent a powerful episode of recent selection in humans.

Source Information

From the Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology (S.M., J. Whitfield, M.P., P.S., J.U., T.C., H.A.-D., H.H., J.B., M.P.A., J.C.); the Genome Centre, Barts and the London Queen Mary's School of Medicine and Dentistry, John Vane Science Centre (C.A.M.); and the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine (C.V., J. Whittaker) — all in London; Papua New Guinea Institute of Medical Research, Goroka, Eastern Highlands Province, Papua New Guinea (J. Whitfield, M.P.A.); and the Centre for International Health, Curtin University, Perth, WA, Australia (M.P.A.).

Address reprint requests to Dr. Collinge at the Department of Neurodegenerative Disease, Institute of Neurology, Queen Sq., London WC1N 3BG, United Kingdom, or at j.collinge@prion.ucl.ac.uk.


http://content.nejm.org/cgi/content/short/361/21/2056



Brain disease “resistance gene” could offer insights into CJD19 November 2009 A community in Papua New Guinea that suffered a major epidemic of a CJD-like fatal brain disease called kuru has developed strong genetic resistance to the disease, according to new research by Medical Research Council (MRC) scientists.

Kuru is a fatal prion disease, similar to CJD in humans and BSE in animals, and is geographically unique to an area in Papua New Guinea. In the mid 20th Century, an epidemic of kuru devastated a population in the Eastern Highlands of Papua New Guinea. The infection was passed on at mortuary feasts, where mainly women and children consumed their deceased relatives as a mark of respect and mourning. This practice was banned and ceased in the late 1950s.

Scientists from the MRC Prion Unit, a national centre of excellence in prion diseases, assessed over 3000 people from the affected and surrounding Eastern Highland populations, including 709 who had participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru. They discovered a novel and unique variation in the prion protein gene called G127V in people from the Purosa valley region where kuru was most rife.

This gene mutation, which is found nowhere else in the world, seems to offer high or even complete protection against the development of kuru and has become frequent in this area through natural selection over recent history, in direct response to the epidemic. This is thought be perhaps the strongest example yet of recent natural selection in humans.

Lead author Professor John Collinge, Director of the MRC Prion Unit said:

“It’s absolutely fascinating to see Darwinian principles at work here. This community of people has developed their own biologically unique response to a truly terrible epidemic. The fact that this genetic evolution has happened in a matter of decades is remarkable. Kuru comes from the same disease family as CJD so the discovery of this powerful resistance factor opens up new areas for research taking us closer to understanding, treating and hopefully preventing a range of prion diseases.”

The study “A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure”, which began in 1996, will be published in the New England Journal of Medicine on 19 November 2009.

ENDS

Notes to editors 1. Study available on request.

2. For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including the first antibiotic penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk

3. Prion diseases or transmissible spongiform encephalopathies (TSEs) belong to group of progressive conditions that affect the nervous system in humans and animals. In humans, prion diseases impair brain function, causing memory changes, personality changes, a decline in intellectual function (dementia), and problems with movement that worsen over time. They are fatal conditions. Familial prion diseases of humans include classic Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS) fatal insomnia (FI) and Kuru.

4. Kuru was restricted to the Fore linguistic groups and their immediate neighbours which whom they intermarried. It was the practice in the Fore society for kinship groups to consume deceased relatives at mortuary feasts, a practice that resulted in human-to-human prion transmission. On the whole, men and children over 8 years of age did not participate in the feast, with the result that kuru at its peak predominantly affected women and children. As recorded in oral history the first cases appeared in the early 20th century and thereafter the number of cases increased in incidence. A peak annual mortality of more than 2% was recorded in some villages. Some villages became largely devoid of young women. More information on the Papua New Guinea Institute of Medical Research is available here www.pngimr.org.pg.

5. The study was lead by the Medical Research Council Prion Unit, and involved scientists from the University College London Institute of Neurology; Papua New Guinea Institute of Medical Research; and Curtin University Australia. Other institutions participating; the Genome Centre, Barts the London Queen Mary’s School of Medicine and Dentistry; London School of Hygiene and Tropical Medicine.

Press contact: 020 7637 6011 press.office@headoffice.mrc.ac.uk


http://www.mrc.ac.uk/Newspublications/News/MRC006502





November 19, 2009

Brain-eating tribe enriches understanding of mad cow disease

Mark Henderson, Science Editor Recommend? A cannibalistic ritual in which the brains of dead tribespeople were eaten by their relatives has triggered one of the most striking examples of rapid human evolution on record, scientists have discovered.

In the middle of the 20th century the Fore tribe of the Eastern Highlands province of Papua New Guinea was devastated by a CJD-like disease called kuru, which was passed on by mortuary feasts in which the brains of the dead were consumed.

Although the practice was banned in the 1950s and kuru has disappeared, it has left an imprint on the tribe’s DNA. Research has now identified a genetic mutation unique to the Fore that protects against the brain disease and which has spread swiftly through the population by natural selection.

As the mutation confers high or almost complete resistance to kuru, carriers have a survival advantage and have had more descendants. About 8 per cent of people from the Purosa Valley region, where kuru hit hardest, now have the gene, which is unknown anywhere else in the world.

Related Links Daniel Gajdusek New wave of mad cow disease feared What the cannibals taught us The findings, from a team led by Simon Mead, of the Medical Research Council Prion Unit at University College London, show how quickly human evolution can respond to new environmental pressures.

They are described today in The New England Journal of Medicine as scientists prepare to celebrate the 150th anniversary of the publication of Charles Darwin’s On the Origin of Species on Tuesday.

Professor John Collinge, the director of the prion unit, said: “It’s absolutely fascinating to see Darwinian principles at work here. This community of people have developed their own biologically unique response to a truly terrible epidemic. The fact that this genetic evolution has happened in a matter of decades is remarkable.”

The research is also significant because it promises to shed light on the rogue prion proteins that cause Creutzfeldt-Jakob disease (vCJD), the human form of mad cow disease.

Dr Mead said: “It isn’t going to lead to a drug tomorrow but it would improve our background understanding of how prion diseases work and how they might be prevented.”

Oral histories provided by elderly members of the Fore tribe suggest that kuru emerged in the early 20th century and developed into a serious epidemic with an annual mortality rate of more than 2 per cent in some villages.

It mainly affected women and children, who would eat the remains of dead relatives. Kuru disappeared when cannibal rituals were stopped in the 1950s under the influence of missionaries.

In the new study scientists analysed the DNA of more than 3,000 people from affected and unaffected parts of the Eastern Highlands, including 709 who had taken part in cannibalistic rituals and 152 who had died of kuru.

The variant in the prion protein gene, called G127V, appears to have emerged about 1800 and then became advantageous with the arrival of kuru.

Dr Mead said that the variant would have spread rapidly for two reasons: “First, if you’re a carrier you’re resistant to the disease. More subtly, it also had benefits in terms of the relatives eaten. If you were in a family protected against kuru and ate auntie’s brain you were less likely to be eating an infected brain.”

In the genes

Sickle-cell anaemia This genetic disease is more common among African and Mediterranean people because the gene responsible also confers resistance to malaria

Blood groups People with blood group O are more vulnerable to cholera but less susceptible to malaria, spread by mosquitoes

HIV There is evidence that a variant of a gene called CCR5-32, which offers resistance against HIV, is increasing in frequency in Africa

Lactose tolerance Common in ethnic groups with a strong pastoral tradition such as North Europeans and East Africans

Skin colour Natural selection favours dark skins at equatorial latitudes for cancer protection, but pale skins at high latitudes, because they allow greater production of vitamin D

Source: Times database


http://www.timesonline.co.uk/tol/news/science/biology_evolution/article6922057.ece




Tuesday, July 28, 2009

The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents


http://kuru-tse.blogspot.com/2009/07/kuru-infectious-agent-is-unique.html




Kuru in the 21st century—an acquired human prion disease Thu Jun 22, 2006 19:44 70.110.82.186

The Lancet 2006; 367:2068-2074

DOI:10.1016/S0140-6736(06)68930-7

Kuru in the 21st century—an acquired human prion disease with very long incubation periods John Collinge a , Jerome Whitfield a b, Edward McKintosh a, John Beck a, Simon Mead a, Dafydd J Thomas a and Michael P Alpers a c

Summary Background Kuru provides the principal experience of epidemic human prion disease. Its incidence has steadily fallen after the abrupt cessation of its route of transmission (endocannibalism) in Papua New Guinea in the 1950s. The onset of variant Creutzfeldt-Jakob disease (vCJD), and the unknown prevalence of infection after the extensive dietary exposure to bovine spongiform encephalopathy (BSE) prions in the UK, has led to renewed interest in kuru. We investigated possible incubation periods, pathogenesis, and genetic susceptibility factors in kuru patients in Papua New Guinea.

Methods We strengthened active kuru surveillance in 1996 with an expanded field team to investigate all suspected patients. Detailed histories of residence and exposure to mortuary feasts were obtained together with serial neurological examination, if possible.

Findings We identified 11 patients with kuru from July, 1996, to June, 2004, all living in the South Fore. All patients were born before the cessation of cannibalism in the late 1950s. The minimum estimated incubation periods ranged from 34 to 41 years. However, likely incubation periods in men ranged from 39 to 56 years and could have been up to 7 years longer. PRNP analysis showed that most patients with kuru were heterozygous at polymorphic codon 129, a genotype associated with extended incubation periods and resistance to prion disease.

Interpretation Incubation periods of infection with human prions can exceed 50 years. In human infection with BSE prions, species-barrier effects, which are characteristic of cross-species transmission, would be expected to further increase the mean and range of incubation periods, compared with recycling of prions within species. These data should inform attempts to model variant CJD epidemiology.

Affiliations

a. MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, UK b. Papua New Guinea Institute of Medical Research, Goroka, EHP, Papua New Guinea c. Centre for International Health, Curtin University, Perth, Australia

Correspondence to: Prof John Collinge

http://www.thelancet.com/journals/lancet/article/PIIS0140673606689307/abstract


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Listen to The Lancet This week's audio summary discusses an Article entitled "Kuru in the 21st century - an acquired human prion disease with very long incubation periods". Also covered is a Lecture assessing climate change and its impact on health, and an Editorial about the roll-out of cervical cancer vaccines worldwide. >>

http://www.thelancet.com/webfiles/images/clusters/thelancet/audio/24June2006.mp3


further into this study;

Discussion

The early clinical, epidemiological, and anthropological study of kuru; the recognition of its neuropathological, and then causal parallels to ovine scrapie;20 and then crucially, the experimental transmission of the disease

to primates,21 originated the concept of the human transmissible spongiform encephalopathies, which was followed in turn by the eventual unifying concept of the mammalian prion diseases. However, in addition to the central historical importance of kuru, study of the end-stage of this epidemic offers a unique opportunity to study the variables of a near-complete epidemic of human prion disease. In particular, recognition of the incubation periods possible after natural prion infection in people is important in providing an insight (from actual case histories rather than from mathematical models) into the probable span of the vCJD epidemic in the UK. Although estimation of kuru incubation periods early in the epidemic was difficult, and the timing of the actual infecting event for an individual can rarely be determined, the abrupt and permanent interruption of the source of infection, endocannibalism, in the late 1950s, has progressively allowed recognition of an enormous span of possible incubation periods, at its shortest extreme bracketed by the rare onset of disease in children as young as 5 years and extending up to (and perhaps beyond) the incubations covering more than half a century, as we describe here.In our field studies, we have interviewed many individuals who participated in traditional mortuary feasting or who described the participation of family members from the preceding generation. These detailed descriptions will be published elsewhere but have reaffirmed the oral histories of endocannibalism in the Fore recorded previously12,22–24 and that this practice ceased abruptly at the time of Australian administrative control over the kuru areas. Although isolated events might have occurred for a few years after this prohibition, we are confident that new exposures of individuals to kuru at mortuary feasts would not have occurred after 1960. Not only have no cases of kuru been recorded in people born after 1959 (and only nine were recorded in those born after 1956); but also all the 11 last recorded cases of kuru that we report here were born before 1950. If any source of infection remained, whether from surreptitious cannibalism, possible ground contam-ination with human prions at sites where food was prepared, or other lateral routes, we would expect individuals born after this period to have kuru—especially since children are thought to have had shorter incubation periods than adults. However, no such cases have been observed. Additionally, although a fraction of hamster-adapted scrapie prions have been shown to survive in soil for at least 3 years,25 the mortuary feast practices (during which the entire body would be consumed) were undertaken so that any substantial contamination of soil would not have occurred, and traditional bamboo knives and leaf plates were burned after the feast. Furthermore, no clusters of kuru cases, as seen earlier in the epidemic,26 have been recorded for many years. We have also reviewed the assertion that maternal transmission of kuru did not occur, and saw no evidence for maternal transmission from kuru archives, interviews of colleagues who have practised medicine in the Fore, or local oral history. Again, any possible vertical route of kuru transmission would have resulted in the presence of kuru in children born after 1960, especially since kuru was common in women of childbearing age; no such cases have occurred.With respect to extrapolation of incubation periods of BSE prion infection in people, we should recognise that the kuru epidemic arose from intraspecies recycling of infectious prions. However, transmission of prions between different mammalian species is associated with a species barrier, which is better described as a transmission barrier, because of the importance of within-species prion strain type, in addition to species-specific differences in its determination.27 The biological effects of such a barrier are: extended mean incubation period; increased spread of incubation periods in individual animals; and reduced attack rate (in which only a fraction of inoculated animals will succumb), by comparison with the 100% mortality generally associated with within-species inoculation with high-titre infectivity. Incubation periods approaching the natural lifespan of the inoculated species are often seen in such primary cross-species transmissions of prions. Second and subsequent passage of prions within the new species is always associated with adaptation involving a considerable shortening of the mean and spread of incubation periods and high or total lethality to high-titre inocula. Thus, estimation of the range of possible incubation periods in human BSE infection needs superimposition of the effect of a transmission barrier onto these findings of natural human incubation periods. The mean incubation period for kuru has been estimated to be around 12 years,27 with a similar estimate in iatrogenic CJD associated with the use of human-cadaver-derived pituitary growth hormone.28 As shown here, maximum incubation periods in kuru can exceed 50 years. The transmission barrier of BSE between cattle and human beings is unknown and cannot be directly measured. However, the cattle-to-mouse barrier for BSE has been well characterised experimentally by comparative endpoint titration. BSE prions transmit readily to laboratory mice, including after oral dosing.29 The murine LD50 (lethal dose causing 50% mortality) in C57Bl/6 mice is about 500-fold higher than that in cattle;30 this barrier also results in a three-fold to four-fold increase in mean incubation period.27 Mean incubation periods of human BSE infection of 30 years or more should therefore be regarded as possible, if not probable,27 with the longest incubation periods approaching (and perhaps exceeding) the typical human lifespan. The shortest incubation periods in kuru were estimated from the age of the youngest patients—suggesting that the shortest incubation period was Articles www.thelancet.com Vol 367 June 24, 2006 2073 4–5 years. Similarly in vCJD, although the total clinical caseload so far has been small, the youngest onsets of vCJD have been at age 12 years or above, providing an early estimate of a minimum incubation period. Furthermore, prion disease in mice follows a well-defined course with a highly distinctive and repeatable incubation time for a specific prion strain in a defined inbred mouse line. In addition to the PrP gene, a few additional genetic loci with a major effect on incubation period have been mapped.4,31,32 Human homologues of such loci could be important in human susceptibility to prion disease, both after accidental human prion exposure and after exposure to the BSE agent. By definition, patients identified so far with vCJD are those with the shortest incubation periods for BSE. These patients could have received an especially high dose of BSE prions. However, no unusual history of dietary, occupational, or other exposure to BSE has been reported from case-control studies. Because of the powerful genetic effects on incubation period in laboratory animals, vCJD patients identified could represent a distinct genetic subpopulation with unusually short incubation periods to BSE prions, with vCJD so far occurring predominantly in those individuals with short incubation time alleles at these multiple genetic loci, in addition to having the homozygous PRNP genotype of codon 129 methionine. Therefore, a human BSE epidemic may be multiphasic, and recent estimates of the size of the vCJD epidemic based on uniform genetic susceptibility could be substantial underestimations.33,34 Genes implicated in species-barrier effects, which would further increase both the mean and range of human BSE incubation periods, are also probably relevant. In this context, a human epidemic will be difficult to accurately model until such modifier loci are identified and their gene frequencies in the population can be measured.4Heterozygosity at PRNP codon 129 is a major determinant of susceptibility to and incubation time of human prion diseases.5,7,9,35 As expected, most of these recent kuru cases with extended incubation periods (eight of ten) were heterozygotes. We have reported previously that most elderly survivors of exposure to traditional mortuary feasts are heterozygous.9 Although the study included a small number of patients with kuru with long incubation periods, we saw no evidence of association with PRNP haplotype,10 HLA-DQ7,18 APOE,36 or PRND alleles.13

Contributors

J Whitfield led the field patrol team throughout the study and investigated all suspect cases; E McKintosh provided assistance during this time. J Beck and S Mead undertook the molecular genetic studies. J Collinge, M P Alpers, E McKintosh, and D J Thomas did field neurological examinations. J Collinge and M P Alpers supervised the study and drafted the manuscript. All authors contributed to and approved the final version of the manuscript. .........

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Posted by: Terry S. Singeltary Sr. July 25, 2006 07:05 PM


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