Homozygous R136S mutation in PRNP gene causes inherited early onset prion disease
Ximelis, Teresa (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Marín-Moreno, Alba (Centro de Investigación en Sanidad Animal (CISA-INIA-CSIC))
Espinosa, J. C. (Centro de Investigación en Sanidad Animal (CISA-INIA-CSIC))
Eraña, Hasier (Center for Cooperative Research in Biosciences (CIC bioGUNE). Basque Research and Technology Alliance (BRTA))
Charco, Jorge M. (Center for Cooperative Research in Biosciences (CIC bioGUNE). Basque Research and Technology Alliance (BRTA))
Hernández, Isabel (Ace Alzheimer Center Barcelona)
Riveira, Carmen (Neurology Service. Hospital de León)
Alcolea, Daniel (Institut d'Investigació Biomèdica Sant Pau)
González-Roca, Eva (Hospital Clínic i Provincial de Barcelona)
Aldecoa, Iban (Hospital Clínic i Provincial de Barcelona)
Molina-Porcel, Laura (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Parchi, Piero (IRCCS. Istituto delle Scienze Neurologiche di Bologna)
Rossi, Marcello (IRCCS. Istituto delle Scienze Neurologiche di Bologna)
Castilla, Joaquín (IKERBasque Basque Foundation for Science)
Ruiz-García, Raquel (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Gelpi, Ellen (Medical University of Vienna)
Torres, Juan María (Centro de Investigación en Sanidad Animal (CISA-INIA-CSIC))
Sanchez-Valle, Raquel (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Universitat Autònoma de Barcelona

Date:	2021
Abstract:	Background: More than 40 pathogenic heterozygous PRNP mutations causing inherited prion diseases have been identified to date. Recessive inherited prion disease has not been described to date. Methods: We describe the clinical and neuropathological data of inherited early-onset prion disease caused by the rare PRNP homozygous mutation R136S. In vitro PrP propagation studies were performed using recombinant-adapted protein misfolding cyclic amplification technique. Brain material from two R136S homozygous patients was intracranially inoculated in TgMet129 and TgVal129 transgenic mice to assess the transmissibility of this rare inherited form of prion disease. Results: The index case presented symptoms of early-onset dementia beginning at the age of 49 and died at the age of 53. Neuropathological evaluation of the proband revealed abundant multicentric PrP plaques and Western blotting revealed a ~ 8 kDa protease-resistant, unglycosylated PrP fragment, consistent with a Gerstmann-Sträussler-Scheinker phenotype. Her youngest sibling suffered from progressive cognitive decline, motor impairment, and myoclonus with onset in her late 30s and died at the age of 48. Genetic analysis revealed the presence of the R136S mutation in homozygosis in the two affected subjects linked to homozygous methionine at codon 129. One sibling carrying the heterozygous R136S mutation, linked to homozygous methionine at codon 129, is still asymptomatic at the age of 74. The inoculation of human brain homogenates from our index case and an independent case from a Portuguese family with the same mutation in transgenic mice expressing human PrP and in vitro propagation of PrP studies failed to show disease transmissibility. Conclusion: In conclusion, biallelic R136S substitution is a rare variant that produces inherited early-onset human prion disease with a Gerstmann-Sträussler-Scheinker neuropathological and molecular signature. Even if the R136S variant is predicted to be "probably damaging", heterozygous carriers are protected, at least from an early onset providing evidence for a potentially recessive pattern of inheritance in human prion diseases.
Grants:	Instituto de Salud Carlos III PI20/00448 Ministerio de Ciencia e Innovación PDI2019-105837RB-I00 Ministerio de Ciencia e Innovación RTI2018-098515-B-I00
Note:	Altres ajuts: Fundació la Marató de TV3/201821-31
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Alzheimer's research & therapy, Vol. 13 Núm. 1 (december 2021) , p. 176, ISSN 1758-9193

DOI: 10.1186/s13195-021-00912-6
PMID: 34663460

13 p, 3.2 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles