Phenotype-genotype studies in kuru: Implications for new variant Creutzfeldt–Jakob disease
Open accessAbstract
The PRNP polymorphic (methionine/valine) codon 129 genotype influences the phenotypic features of transmissible spongiform encephalopathy. All tested cases of new variant Creutzfeldt–Jakob disease (nvCJD) have been homozygous for methionine, and it is conjectural whether different genotypes, if they appear, might have distinctive phenotypes and implications for the future “epidemic curve” of nvCJD. Genotype-phenotype studies of kuru, the only other orally transmitted transmissible spongiform encephalopathy, might be instructive in predicting the answers to these questions. We therefore extracted DNA from blood clots or sera from 92 kuru patients, and analyzed their codon 129 PRNP genotypes with respect to the age at onset and duration of illness and, in nine cases, to detailed clinical and neuropathology data. Homozygosity at codon 129 (particularly for methionine) was associated with an earlier age at onset and a shorter duration of illness than was heterozygosity, but other clinical characteristics were similar for all genotypes. In the nine neuropathologically examined cases, the presence of histologically recognizable plaques was limited to cases carrying at least one methionine allele (three homozygotes and one heterozygote). If nvCJD behaves like kuru, future cases (with longer incubation periods) may begin to occur in older individuals with heterozygous codon 129 genotypes and signal a maturing evolution of the nvCJD “epidemic.” The clinical phenotype of such cases should be similar to that of homozygous cases, but may have less (or at least less readily identified) amyloid plaque formation.
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The Met/Met genotype depletion in survivors was associated with increased susceptibility of 129 Met/Met carriers, who became early victims of the epidemic and disproportionally died after the shortest incubation time.
“This phenomenon was associated with increased susceptibility of the 129 Met/Met carriers who became early victims of the epidemic, disproportionally dying of the disease after the shortest incubation time (24, 37).”
From Kuru (2012) · cites this paper as [24]
The Results report that Met/Met kuru patients were overrepresented among younger cases, and the Discussion infers that homozygotes probably had shorter incubation periods than heterozygotes. The paper does not establish increased susceptibility or depletion of Met/Met survivors, and it presents the shorter incubation period as probable rather than measured. (LLM, conf=0.85)
Experimental — accuracy not yet measured129 Met/Val and Val/Val carriers developed kuru at a later age, after an incubation period of 20 years or longer, and many survived the epidemic.
“Based on representative statistics, it was concluded that individuals homozygous for the 129 Met allele had an earlier age of disease onset and a shorter incubation time, whereas 129 Met/Val and Val/Val carriers developed kuru at a later age, after an incubation period of 20 years or longer, and many survived the epidemic (24).”
From Kuru (2012) · cites this paper as [24]
The Results (page not provided) show that Met/Val patients were overrepresented in older age groups, and the Discussion infers that heterozygotes probably had longer incubation periods than homozygotes. The Results do not show later onset for Val/Val patients; Table 1 includes more Val/Val cases under age 15 than over age 30. The paper does not establish an incubation period of 20 years or longer or report that many carriers survived the epidemic. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIndividuals homozygous for the 129 Met allele had an earlier age of disease onset and a shorter incubation time.
“Based on representative statistics, it was concluded that individuals homozygous for the 129 Met allele had an earlier age of disease onset and a shorter incubation time, whereas 129 Met/Val and Val/Val carriers developed kuru at a later age, after an incubation period of 20 years or longer, and many survived the epidemic (24).”
From Kuru (2012) · cites this paper as [24]
The Results report that Met/Met kuru patients were overrepresented at younger ages of onset, while the Discussion infers that homozygotes probably had a shorter incubation period than heterozygotes. The claim presents that inference as certain. The Results do not support grouping Val/Val carriers with Met/Val carriers as developing kuru later, and the paper does not establish a 20-year incubation period or that many carriers survived the epidemic. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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“This phenomenon was associated with increased susceptibility of the 129 Met/Met carriers who became early victims of the epidemic, disproportionally dying of the disease after the shortest incubation time (24, 37).”
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- Authors
- Cervenáková, L., Goldfarb, L. G., Garruto, R., Lee, H.-S., Gajdusek, D. C., & Brown, P.
- Affiliations
- Laboratory of Central Nervous System Studies and Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; American Red Cross, J. H. Holland Laboratory, Rockville, MD 20855; and Department of Anthropology, State University of New York, Binghamton, NY 13902
- Binghamton University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-10-27
- Volume
- 95
- Issue
- 22
- Pages
- 13239-13241
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC23768
- OpenAlex
- W2161225587
- Cited by
- 160
- References
- 0
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 2 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 5
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- kuru, variant Creutzfeldt-Jakob disease, PRNP codon 129 polymorphism, genotype-phenotype correlation, prion disease, age of onset, disease duration, amyloid plaques, neuropathology, incubation period, epidemic curve
- MeSH terms
- Prion Proteins, Adolescent, Adult, Amyloid, Child, Chromosomes, Human, Pair 20, Codon, DNA, Female, Genotype, Humans, Creutzfeldt-Jakob Syndrome, Kuru, Male, Methionine, Middle Aged, Papua New Guinea, Phenotype, Prions, Protein Precursors, Retrospective Studies, Valine, Genetic Variation, Point Mutation, Age of Onset
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