Homozygous R136S mutation in PRNP gene causes inherited early onset prion disease
Por:
Ximelis, T, Marin-Moreno, A, Espinosa, JC, Erana, H, Charco, JM, Hernandez, I, Riveira, C, Alcolea, D, Gonzalez-Roca, E, Aldecoa, I, Molina-Porcel, L, Parchi, P, Rossi, M, Castilla, J, Ruiz-Garcia, R, Gelpi, E, Torres, JM, Sanchez-Valle, R
Publicada:
18 oct 2021
Resumen:
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 PrPSc 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 similar to 8 kDa protease-resistant, unglycosylated PrPSc fragment, consistent with a Gerstmann-Straussler-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 PrPSc 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-Straussler-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.
Filiaciones:
Ximelis, T:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Hosp Clin, Biobanc, Neurol Tissue Bank, Barcelona 08036, Spain
Marin-Moreno, A:
Ctr Invest Sanidad Anim CISA INIA CSIC, Madrid 28130, Spain
Espinosa, JC:
Ctr Invest Sanidad Anim CISA INIA CSIC, Madrid 28130, Spain
Erana, H:
Basque Res & Technol Alliance BRTA, Ctr Cooperat Res Biosci CIC BioGUNE, Bizkaia Technol Pk, Derio 48160, Spain
Charco, JM:
Basque Res & Technol Alliance BRTA, Ctr Cooperat Res Biosci CIC BioGUNE, Bizkaia Technol Pk, Derio 48160, Spain
Hernandez, I:
Barcelona Alzheimer Treatment & Res Ctr, Fundacio ACE, Barcelona 08028, Spain
Riveira, C:
Hosp Leon, Neurol Serv, Leon 24071, Spain
Alcolea, D:
Hosp Santa Creu & Sant Pau, Memory Unit, Barcelona 08041, Spain
Gonzalez-Roca, E:
Hosp Clin Barcelona, Biomed Diagnost Ctr, Immunol Dept, Barcelona 08036, Spain
Aldecoa, I:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Hosp Clin, Biobanc, Neurol Tissue Bank, Barcelona 08036, Spain
Univ Barcelona, Hosp Clin Barcelona, Biomed Diagnost Ctr, Pathol Dept, Barcelona 08036, Spain
Molina-Porcel, L:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Hosp Clin, Biobanc, Neurol Tissue Bank, Barcelona 08036, Spain
Univ Barcelona, IDIBAPS, Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit,Neur, Villarroel 170, Barcelona 08036, Spain
Parchi, P:
Univ Bologna, Dept Expt Diagnost & Specialty Med DIMES, I-40138 Bologna, Italy
IRCCS, Ist Sci Neurol Bologna, I-40139 Bologna, Italy
Rossi, M:
IRCCS, Ist Sci Neurol Bologna, I-40139 Bologna, Italy
Castilla, J:
Basque Res & Technol Alliance BRTA, Ctr Cooperat Res Biosci CIC BioGUNE, Bizkaia Technol Pk, Derio 48160, Spain
IKERBasque Basque Fdn Sci, Bilbao 48009, Spain
Ruiz-Garcia, R:
Hosp Clin Barcelona, Biomed Diagnost Ctr, Immunol Dept, Barcelona 08036, Spain
Univ Barcelona, IDIBAPS, Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit,Neur, Villarroel 170, Barcelona 08036, Spain
Gelpi, E:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Hosp Clin, Biobanc, Neurol Tissue Bank, Barcelona 08036, Spain
Med Univ Vienna, Dept Neurol, Div Neuropathol & Neurochem, A-1090 Vienna, Austria
Torres, JM:
Ctr Invest Sanidad Anim CISA INIA CSIC, Madrid 28130, Spain
Sanchez-Valle, R:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Hosp Clin, Biobanc, Neurol Tissue Bank, Barcelona 08036, Spain
Univ Barcelona, IDIBAPS, Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit,Neur, Villarroel 170, Barcelona 08036, Spain
gold, Green Published
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