PRNP – Gerstmann-Straussler-Scheinker syndrome

The cellular prion protein gene PRNP is causally linked to Gerstmann-Straussler-Scheinker syndrome, an autosomal dominant prion disorder. Clinical validity is rated as Strong based on segregation of missense variants in four unrelated kindreds, involving at least 12 affected relatives and over a dozen probands displaying consistent cerebellar ataxia and cognitive decline (12 probands,[PMID:11071439]; seven relatives,[PMID:28416787]; five relatives,[PMID:22211828]; one proband each,[PMID:24814844],[PMID:31890235]).

Inheritance is fully penetrant autosomal dominant, with segregation documented in multiple families. Segregation analysis identified at least 12 additional affected relatives carrying pathogenic PRNP variants, including P102L and P84S, co-segregating with disease phenotype ([PMID:28416787]; [PMID:24814844]). Case series encompass 12 probands presenting with progressive cerebellar ataxia (HP:0002066; HP:0001251), dysarthria (HP:0001260), unsteady gait (HP:0002317), and later dementia (HP:0000726). Variant spectrum is dominated by missense substitutions in the globular C-terminal domain, with recurrent c.305C>T (p.Pro102Leu) in four kindreds and c.250C>T (p.Pro84Ser) in a sporadic index case.

Functional studies support a toxic gain-of-function mechanism. Molecular dynamics simulations of the A117V variant peptide revealed helix destabilization conducive to beta-sheet conversion ([PMID:9383432]). In cell models, the Y145Ter mutant exhibited rapid proteasomal degradation yet accumulated as detergent-insoluble, proteinase-resistant aggregates when turnover was impaired ([PMID:10438517]). Cell-free assays showed that the Q218K variant acts dominantly to inhibit wild-type fibril formation, indicating aberrant intermolecular interactions during prion propagation ([PMID:17766375]).

No conflicting evidence disputing PRNP’s role in GSS has been reported. Genetic and biochemical concordance across kindreds, consistent segregation, and mechanistic assays provide a coherent pathogenic narrative. Additional data exceeding ClinGen scoring include extensive in vitro amyloidogenesis and transgenic mouse models but do not alter the strong clinical classification.

Key Take-home: Heterozygous missense PRNP variants—principally p.Pro102Leu—are robust diagnostic markers for Gerstmann-Straussler-Scheinker syndrome, guiding genetic testing and family screening.

References

• Chemistry & biology • 1995 • Theoretical studies of sequence effects on the conformational properties of a fragment of the prion protein: implications for scrapie formation. PMID:9383432
• The Journal of biological chemistry • 1999 • Proteasomal degradation and N-terminal protease resistance of the codon 145 mutant prion protein. PMID:10438517
• Neuroradiology • 2000 • Proton magnetic resonance spectroscopy of a patient with Gerstmann-Straussler-Scheinker disease. PMID:11071439
• Protein science : a publication of the Protein Society • 2007 • The dominant-negative effect of the Q218K variant of the prion protein does not require protein X. PMID:17766375
• Acta neurologica Scandinavica • 2012 • Divergent clinical and neuropathological phenotype in a Gerstmann-StrÃ…ussler-Scheinker P102L family PMID:22211828
• Neurology • 2014 • Gerstmann-Straussler-Scheinker disease: novel PRNP mutation and VGKC-complex antibodies PMID:24814844
• Neurosciences (Riyadh, Saudi Arabia) • 2017 • A family with hereditary cerebellar ataxia finally confirmed as Gerstmann-Straussler-Scheinker syndrome with P102L mutation in PRNP gene. PMID:28416787
• Journal of clinical movement disorders • 2019 • A case of Gerstmann-Straussler-Scheinker (GSS) disease with supranuclear gaze palsy. PMID:31890235

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