PRNP – Inherited Creutzfeldt-Jakob Disease

Inherited Creutzfeldt-Jakob disease (fCJD) is an autosomal dominant prionopathy caused by pathogenic variants in PRNP. Familial cases have been reported in multi-generation pedigrees, including a kindred with five affected members carrying a codon 178 missense substitution and a 24-bp deletion in the octapeptide repeat region, implicating D178N in disease pathogenesis (PMID:1357594). A large cluster of African American kindreds demonstrated 8 confirmed and 13 suspected cases across seven generations, underscoring AD segregation and enabling predictive testing (PMID:27997483).

Genetic evidence encompasses over 500 reported PRNP mutations in fCJD, including missense changes (e.g., P102L, R148H, V180I) and octapeptide repeat insertions, with consistent co-segregation in unrelated families and absence in healthy controls (PMID:12420099; PMID:16314483). The R148H variant (c.443G>A (p.Arg148His)) has been documented as de novo or inherited with complete penetrance except for rare late-onset nonpenetrance (PMID:16314483).

Functional studies support a toxic gain-of-function mechanism. Molecular dynamics and NMR of D178N and E200K variants reveal minimal global folding changes but altered surface electrostatics and helix stability favoring beta-rich oligomerization (PMID:10954699; PMID:11775003). Cell models of E200K demonstrate aberrant glycosylation and impaired trafficking, leading to proteasome-resistant PrP accumulation (PMID:10438517; PMID:10934164).

Incomplete penetrance has been observed for codon 188 variants (e.g., T188K) where an obligate carrier remained asymptomatic at age 79, indicating modifier effects of codon 129 and other factors (PMID:18478114).

Together, genetic and experimental findings establish PRNP mutations as definitively causal for fCJD. Clinical utility includes genetic counseling, presymptomatic testing, and informed decision-making for at-risk relatives. Key Take-home: AD PRNP variants drive misfolding and neurodegeneration in fCJD, warranting early genetic evaluation and family screening.

References

• Neurology • 1992 • A PrP gene codon 178 base substitution and a 24-bp interstitial deletion in familial Creutzfeldt-Jakob disease PMID:1357594
• Journal of public health management and practice • 2017 • Familial Creutzfeldt-Jakob Disease Cluster Among an African American Family PMID:27997483
• Journal of neurology • 2002 • Mutations of the prion protein gene phenotypic spectrum PMID:12420099
• The American journal of pathology • 2005 • Creutzfeldt-Jakob disease (CJD) with a mutation at codon 148 of prion protein gene: relationship with sporadic CJD PMID:16314483
• The Journal of biological chemistry • 2000 • Solution structure of the E200K variant of human prion protein. Implications for the mechanism of pathogenesis in familial prion diseases PMID:10954699
• Journal of molecular graphics & modelling • 2001 • Flexibility of the murine prion protein and its Asp178Asn mutant investigated by molecular dynamics simulations PMID:11775003
• The Journal of biological chemistry • 1999 • Proteasomal degradation and N-terminal protease resistance of the codon 145 mutant prion protein PMID:10438517
• The American journal of pathology • 2000 • Effect of the E200K mutation on prion protein metabolism. Comparative study of a cell model and human brain PMID:10934164
• PloS one • 2008 • Evidence for a pathogenic role of different mutations at codon 188 of PRNP PMID:18478114

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