Extended Data Table 5 Details of PRNP-truncating variants

From: Evaluating drug targets through human loss-of-function genetic variation

  1. Allele count for variants from the literature in Fig. 3c is the total number of definite or probable cases with sequencing performed in the studies cited in this table. The L234Pfs7X variant changes the C-terminal GPI signal of prion protein from SMVLFSSPPVILLISFLIFLIVGX to SMVPSPLHLX. This new sequence does not adhere to the known rules of GPI anchor attachment80: GPI signals must contain a 5–10-polar-residue spacer followed by 15–20 hydrophobic residues. Thus, this frameshifted prion protein would be predicted to be secreted and thus may be pathogenic, explaining the Alzheimer’s disease diagnosis in this individual. However, it is also possible that the new C-terminal sequence found here interferes with prion formation, and/or that this variant is incompletely penetrant, and that the diagnosis of Alzheimer’s disease in this individual is merely a coincidence. The following references are cited in the table: refs. 41,81,82,83,84,85,86,87,88,89.
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