Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the <i>CYP4X1</i> gene

Poleggi, Anna; Lee, Sven J. van der; Capellari, Sabina; Puopolo, Maria; Ladogana, Anna; Pascali, Eleonora De; Lia, Debora; Formato, Alessia; Bartoletti-Stella, Anna; Parchi, Piero; Duijn, Cornelia M. van; Pocchiari, Maurizio

doi:10.1136/jnnp-2018-318756

Cited by 16 publications

(8 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is supported by previous studies, which showed wide variation of PrP expression in healthy control brains [ 23 ]. This may explain why some carriers of the E200K mutation do not develop the disease as well as why the clinical signs [ 24 ], age of clinical onset, and duration of clinical disease vary between individuals [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…Further genetic modifiers may also influence disease onset, duration and signs. For instance, CYP4X1 gene has been recently found to modulate the age of onset in individuals with the E200K mutation [ 25 ]. The influence of genetic background on E200K prion disease is also shown by the difference in the outcomes of the two mouse models of E200K prion disease.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

et al. 2020

View full text Add to dashboard Cite

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In several forms of genetic prion disease, for example those associated with the E200K PRNP mutation, the clinical disease manifestations, PrP res WB signature and tissue PrP res distributions are similar to that in sCJD [34,48]. Despite the ethical issues it might raise, the longitudinal collection of blood samples and body fluids, for research purposes, in consenting patients belonging to families affected by these genetic forms of prion diseases (with confirmed mutations of the PRNP gene) may represent the only possibility to address this question.…”

Section: Iatrogenic Transmission Of Cjdmentioning

confidence: 93%

Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients

et al. 2021

View full text Add to dashboard Cite

Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest human prion disease, occurring most likely as the consequence of spontaneous formation of abnormal prion protein in the central nervous system (CNS). Variant Creutzfeldt–Jakob disease (vCJD) is an acquired prion disease that was first identified in 1996. In marked contrast to vCJD, previous investigations in sCJD revealed either inconsistent levels or an absence of PrPSc in peripheral tissues. These findings contributed to the consensus that risks of transmitting sCJD as a consequence of non-CNS invasive clinical procedures were low. In this study, we systematically measured prion infectivity levels in CNS and peripheral tissues collected from vCJD and sCJD patients. Unexpectedly, prion infectivity was detected in a wide variety of peripheral tissues in sCJD cases. Although the sCJD infectivity levels varied unpredictably in the tissues sampled and between patients, these findings could impact on our perception of the possible transmission risks associated with sCJD.

show abstract

“…The onset and clinical characteristics of Chinese E200K gCJD are more like as sCJD, although the onset age of E200K gCJD is younger than that of sCJD 8,17 . CYP4X1 SNP rs9793471 has an influence on age at onset of disease in patients with E200K genetic and sporadic CJD 18 . In this study, twenty nine cases were CYP4X1 rs9793471 AA genotype, and only one case was GA.…”

Section: Discussionmentioning

confidence: 99%

The genetic Creutzfeldt-Jakob disease with E200K mutation: analysis of clinical, genetic and laboratory features of 30 Chinese patients

Gao

Shi

Xiao

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Genetic Creutzfeldt-Jakob disease (gCJD) with E200K mutation is one of the common subtypes of human genetic prion diseases worldwide. In this study, we systematically analyzed 30 Chinese E200K gCJD cases for their epidemiological, clinical, laboratory and genetic features. The patients came from 12 different provinces, majority in northern part of China. The onset age varied from 42 to 71 year-old (y), with the median of was 57 y. The CYP4X1 gene rs9793471 SNP was tested. Only one patient’s rs9793471 genotype was GA and the others’ were AA. The gender ratio (M: F) was 1:1.73 (11:19). The foremost symptoms and clinical progression of Chinese E200K gCJD patients were quite similar as sporadic CJD cases. Only a few cases (4/30) recalled clearly disease related family history. 74.1% (20/27), 86.7% (26/30) and 50.0% (13/26) of the cases were CSF 14-3-3 positive, sCJD associated abnormalities on MRI and special PSWC on EEG, respectively. The median clinical duration was 9 months (varying from 2 to 26 months). All 30 Chinese E200K gCJD patients were M129M and E219E homozygous. 21 members from 3 families conducted PRNP sequencing and 16 asymptomatic carriers of E200K mutation with M129M and E219E homozygous were identified. This is the largest study on E200K gCJD patients in China, which would benefit to the knowledge of E200K gCJD.

show abstract

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Cited by 16 publications

References 31 publications

Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients

The genetic Creutzfeldt-Jakob disease with E200K mutation: analysis of clinical, genetic and laboratory features of 30 Chinese patients

Contact Info

Product

Resources

About