Research LettersDistribution of codon 129 genotype in human growth hormone-treated CJD patients in France and the UK
Summary
Since homozygosity MM at codon 129 of the prion protein gene is a recognised risk factor in all forms of Creutzfeldt-Jakob disease (CJD), we studied the distribution of codon 129 polymorphism in patients in France and in the UK with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of W homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in UK patients was surprisingly low (4%) compared with that in French patients (62%). There is no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone.
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Cited by (85)
Preventive or promotive effects of PRNP polymorphic heterozygosity on the onset of prion disease
2023, HeliyonThe polymorphic heterozygosity of PRNP at codon 129 or 219 prevents the onset of sporadic Creutzfeldt-Jakob disease (sCJD). We investigated the association between polymorphic genotypes at codon 129 or 219 and comprehensive prion disease onset using non-CJD as a reference. EK heterozygotes at codon 219, versus EE homozygotes, showed a preventive effect on the extensive prion diseases―sCJD, genetic CJD (gCJD) with V180I or M232R mutation, and Gerstmann-Straussler-Scheinker disease with P102L mutation. No preventive effect was observed for E200K-gCJD and dura-grafted CJD (dCJD) in 129 MV and 219 EK heterozygotes. It was suggested that unlike other prion diseases, E200K-gCJD may not benefit from the preventive effect of 219 EK heterozygosity because complementary electrostatic interactions between PrP molecules at K200 and E219 might make homodimer formation easier. Comparison of sCJD and dCJD indicates that 219 EK heterozygosity strongly inhibits de novo synthesis of PrPSc (initial PrPSc formation), but does not inhibit accelerated propagation of existing PrPSc.
Prion diseases or transmissible spongiform encephalopathies
2022, Revue de Medecine InterneLes maladies à prions ou encéphalopathies spongiformes transmissibles (EST) sont des maladies humaines et animales transmissibles naturellement ou expérimentalement avec une longue durée d’incubation et une évolution fatale sans rémission. La nature exacte de l’agent transmissible reste discutée mais l’absence de structure évoquant un micro-organisme conventionnel a conduit Stanley B. Prusiner à émettre l’hypothèse qu’il pourrait s’agir d’une protéine infectieuse (proteinaceous infectious particle ou prion). Le prion serait la forme anormale d’une protéine normale, la PrP cellulaire (PrPc) qui va changer de conformation spatiale et être convertie en protéine prion scrapie (PrPsc) ayant des propriétés de résistance partielle aux protéases, d’agrégation et d’insolubilité dans les détergents. Les EST ne s’accompagnent d’aucune réaction inflammatoire ou immunitaire et se caractérisent par les lésions cérébrales associant spongiose, raréfaction neuronale, gliose astrocytaire et accumulation de la PrPsc pouvant prendre l’aspect de plaques amyloïdes. Si le lien entre l’accumulation de PrPsc et la survenue des lésions est discuté, la présence de PrPsc est constante au cours des EST et sa mise en évidence est nécessaire au diagnostic de certitude. Même si elles restent des maladies rares (2 cas par million), l’identification du kuru, à la fin des années 1950, des cas iatrogènes au courant des années 1970 et de la variante de la maladie de Creutzfeldt-Jakob (MCJ) au milieu des années 1990 expliquent l’intérêt pour ces maladies, mais aussi les craintes qu’elles peuvent faire peser sur la santé publique. Elles demeurent un modèle passionnant de recherche car elles appartiennent à la fois au groupe des maladies neurodégénératives avec accumulation de protéines (MCJ sporadique), au groupe des maladies transmissibles (MCJ iatrogènes, variante de la MCJ) mais aussi au groupe des affections génétiques de transmission mendélienne dominante (MCJ génétiques, syndrome de Gerstmann-Straussler-Scheinker, insomnie fatale familiale).
Prion diseases or transmissible spongiform encephalopathies (TSEs) are human and animal diseases naturally or experimentally transmissible with a long incubation period and a fatal course without remission. The nature of the transmissible agent remains debated but the absence of a structure evoking a conventional microorganism led Stanley B. Prusiner to hypothesize that it could be an infectious protein (proteinaceous infectious particle or prion). The prion would be the abnormal form of a normal protein, cellular PrP (PrPc) which will change its spatial conformation and be converted into scrapie prion protein (PrPsc) with properties of partial resistance to proteases, aggregation and insolubility in detergents. No inflammatory or immune response are detected in TSEs which are characterized by brain damage combining spongiosis, neuronal loss, astrocytic gliosis, and deposits of PrPsc that may appear as amyloid plaques. Although the link between the accumulation of PrPsc and the appearance of lesions remains debated, the presence of PrPsc is constant during TSE and necessary for a definitive diagnosis. Even if they remain rare diseases (2 cases per million), the identification of kuru, at the end of the 1950s, of iatrogenic cases in the course of the 1970s and of the variant of Creutzfeldt-Jakob disease (CJD) in the mid-1990s explain the interest in these diseases but also the fears they can raise for public health. They remain an exciting research model because they belong both to the group of neurodegenerative diseases with protein accumulation (sporadic CJD), to the group of communicable diseases (iatrogenic CJD, variant of CJD) but also to the group of genetic diseases with a transmission Mendelian dominant (genetic CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia).
Genetic risk factors for Creutzfeldt-Jakob disease
2020, Neurobiology of DiseasePrion diseases are a group of fatal neurodegenerative disorders of mammals that share a central role for prion protein (PrP, gene PRNP) in their pathogenesis. Prions are infectious agents that account for the observed transmission of prion diseases between humans and animals in certain circumstances. The prion mechanism invokes a misfolded and multimeric assembly of PrP (a prion) that grows by templating of the normal protein and propagates by fission. Aside from the medical and public health notoriety of acquired prion diseases, the conditions have attracted interest as it has been realized that common neurodegenerative disorders share so-called prion-like mechanisms. In this article we will expand on recent evidence for new genetic loci that alter the risk of human prion disease. The most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), is characterized by the seemingly spontaneous appearance of prions in the brain. Genetic variation within PRNP is associated with all types of prion diseases, in particular, heterozygous genotypes at codons 129 and 219 have long been known to be strong protective factors against sCJD. A large number of rare mutations have been described in PRNP that cause autosomal dominant inherited prion diseases. Two loci recently identified by genome-wide association study increase sCJD risk, including variants in or near to STX6 and GAL3ST1. STX6 encodes syntaxin-6, a component of SNARE complexes with cellular roles that include the fusion of intracellular vesicles with target membranes. GAL3ST1 encodes cerebroside sulfotransferase, the only enzyme that sulfates sphingolipids to make sulfatides, a major lipid component of myelin. We discuss how these roles may modify the pathogenesis of prion diseases and their relevance for other neurodegenerative disorders.
Iatrogenic Creutzfeldt–Jakob disease
2018, Handbook of Clinical NeurologyCitation Excerpt :It is noteworthy that 219 E/K heterozygosity is not protective against dCJD originating from the M1 sCJD strain (Kobayashi et al., 2015b), though this genotype confers resistance against the development of sCJD (Shibuya et al., 1998). In hGH CJD patients in France and the United States, 129 M/M homozygotes and 129 V/V homozygotes have been overrepresented, whereas 129 M/V heterozygotes have been underrepresented (Fig. 12.5) (Brandel et al., 2003; Brown et al., 2012). In addition, these 129M/V heterozygous patients showed significantly longer incubation periods than the homozygous patients (d’Aignaux et al., 1999).
Iatrogenic transmission of Creutzfeldt–Jakob disease (CJD) has occurred through particular medical procedures. Among them, dura mater grafts and pituitary-derived growth hormone obtained from human cadavers undiagnosed as CJD are the most frequent sources of infection. Recent advances in our knowledge about dura mater graft- and human pituitary-derived growth hormone-associated CJD patients have revealed that the combination of the infected CJD strain and the PRNP genotype of the patient determines their clinical, neuropathologic, and biochemical features. In this chapter, we summarize the clinical, neuropathologic, biochemical, and diagnostic features of dura mater graft- and human pituitary-derived growth hormone-associated CJD patients for the appropriate diagnosis of iatrogenic CJD.
Variant Creutzfeldt–Jakob disease
2018, Handbook of Clinical NeurologyVariant CJD (vCJD) was described first in the United Kingdom in 1996. It is a zoonotic form of human prion disease, originating from dietary contamination of human food with material from bovine spongiform encephalopathy (BSE)-affected cattle. It has important epidemiologic, clinical, and neuropathogic differences from other forms of human prion disease. Cases have occurred in several countries but the United Kingdom and France have been most affected. Following the decline in BSE in cattle and the dietary protective measures adopted, vCJD has become an extremely rare disease. However, important concerns remain about asymptomatic infection in human populations (especially the United Kingdom) and the possibility of human-to-human transmission via medical and surgical interventions. Definitive diagnosis depends on neuropathology, usually undertaken at autopsy, but sometimes on brain biopsy. Clinical diagnosis with a reasonable degree of likelihood is, however, possible based on the clinical features and the finding of the pulvinar sign on cerebral magnetic resonance. There are also emerging tests (including blood tests) that have promising sensitivity and specificity for vCJD. It is a progressive illness, inevitably fatal with no curative treatment.
Prion disease
2018, Handbook of Clinical NeurologyGenetic prion diseases (gPrDs) are caused by autosomal-dominant mutations in the prion protein gene (PRNP). Although the first PRNP mutations identified, and most since, are PRNP missense, octapeptide repeat insertions, deletion and nonsense mutations have now also been shown to cause gPrD. Based on clinicopathologic features of familial disease, gPrDs historically have been classified into three forms: familial Jakob–Creutzfeldt disease, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. This classification, however, occurred prior to the identification of PRNP, and although these forms are still recognized, classification now is somewhat more complex. Clinical manifestations, and even pathology, are known to be more heterogeneous and varied than the historic three phenotypic classifications. Most gPrDs either present rapidly with progression of dementia, ataxia, myoclonus, and other motor features leading to death in few months or present more slowly, declining over a few years with mild cognitive impairment, ataxia, or parkinsonism and later dementia; a few very rare mutations, however, present over years to decades with neuropsychiatric disorders and systemic symptoms (gastrointestinal disorders and neuropathy). In this chapter, we review the broad phenotypic spectrum of PRNP mutations causing gPrDs.