Allele count in gnomAD: 3
Cases in literature: 1 (China)
Penetrance calculation: Pathogenicity not established
Mutation reported by Zheng et al in 20081.
Female case found amongst 185 Han Chinese patients diagnosed with sporadic neurodegenerative dementia, with negative family history of neurodegenerative diseases in both first- and second-degree relatives. Clinical symptoms began aged 74 years, when she first reported poor memory and forgetting cooking food, resulting in its burning. The following year, hallucinations and delusions began (the mode and type of which is not reported). She presented aged 76 with reduced visual acuity and deteriorating cognition. She was given a diagnosis of Alzheimer’s disease. She was alive at time of report, aged 77 years (36 months from onset). Family history was unremarkable and genetic analysis could not be undertaken in her parents as they were deceased.
MMSE score of 13/30 at age 77 years. Examination revealed a corticospinal (upper motor neuron) syndrome with bilateral brisk deep tendon reflexes1. No further clinical information is provided.
MR brain imaging showed mild cerebral atrophy1. EEG and CSF 14-3-3 protein analyses not undertaken.
c.290G>A substitution was found leading to the AGT-to-AAT change at codon 97 leading to the Ser97Asn missense mutation. The genotype at codon 129 was homozygous methionine (Met/Met129)1.
Neuropathological studies: n/a
Structure-based protein function annotation:
Serine 97 lies between two functionally important elements: the metal-binding octapeptide repeat region (aa 51-91, including initial nonapeptide) and the second charged cluster (CC2, aa 101-110 – see Architecture of PrP). Serine is a small, polar amino acid with an uncharged side chain, which in this variant, is substituted for asparagine, that is similarly polar and neutral. Adjacent to position 97 is residue His96, which has been shown (along with His111) to also bind copper with high affinity2-5. Mutant Ser97Asn could potentially impart a degree of steric hindrance to the His96 site, however, binding of copper outside of the octapeptide repeat region is not integral to formation of the neuroprotective N-C quaternary fold6 (See Pro84Ser analysis). Therefore, Ser97Asn is a seemingly innocuous substitution that is not expected to malign the structural or functional integrity of PrPC in an obvious way. Indeed, pathogenicity of this mutant is uncertain – the family history is negative and there are insufficient clinical or biochemical data to support a diagnosis of prion disease in the index case. It therefore, may just be that S97N represents a non-pathogenic variant that has coincidentally co-segregated in a patient with Alzheimer’s dementia.
In silico Pathogenicity predictions:
- Probability of pathogenicity: 0.161
- Standard error: 0.047
- Prediction: Neutral
- Score: 0.313
- Prediction: Benign
A stringent REVEL score threshold of 0.75 is applied, above which the variant is classified as pathogenic.
- Zheng L, Longfei J, Xinqing Z et al. PRNP mutations in a series of apparently sporadic neurodegenerative dementias in China. American Journal of Medical Genetics Part B Neuropsychiatric Genetics 2008; 147B(6): 938-944. (PMID: 18425766)
- Burns CS, Aronoff-Spencer E, Legname G et al. Copper coordination in the full-length, recombinant prion protein. Biochemistry 2003; 42(22): 6794-6803. (PMID: 12779334)
- Jackson GS, Murray I, Hosszu LL et al. Location and properties of metal-binding sites on the human prion protein. Proceedings of the National Academy of Sciences USA 2001; 98(15): 8531-8535. (PMID: 11438695)
- Wells MA, Jelinska C, Hosszu LLP et al. Multiple forms of coper (II) co-ordination occur throughout the disordered N-terminal region of the prion protein at pH 7.4. Biochemical Journal 2006; 400(part 3): 501-510. (PMID: 16925523)
- Walter ED, Stevens DJ, Spevacek AR et al. Copper Binding Extrinsic to the Octapeptide Region in the Prion Protein. Current Protein and Peptide Science 2009; 10(5): 529-535. (PMID: 19538144)
- Schilling KM, Tao L, Wu B et al. Both N-Terminal and C-terminal Histidine Residues of the Prion Protein Are Essential for Copper Coordination and Neuroprotective Self-Regulation. Journal of Molecular Biology 2020; 432(16): 4408-4425. (PMID: 32473880)
- Niroula A, Urolagin S, Vihinen M. PON-P2: Prediction Method for Fast and Reliable Identification of Harmful Variants. PLoS One 2015; 10(2): e0117380. (PMID: 25647319)
- Ioannidis NM, Rothstein JH, Pejaver V et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. American Journal of Human Genetics 2016; 99(4): 877-885. (PMID: 27666373)