Technical Research Assistant II
Gannon McDonough, Katherine Morillo, Alana Cheng, Ryan N. Doan, Brian Appleby, Chae Kim, Mark Cohen, Jiri G. Safar, August Yue Huang, Christopher A. Walsh, Michael B. Miller
Michael B. Miller, MD, PhD
Creutzfeldt-Jakob Disease (CJD) is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. While ~1% of cases are transmitted by misfolded PrP, ~15% are inherited, and ~85% are sporadic (sCJD). Familial cases are inherited through germline mutations in PRNP, while the cause of sCJD is unknown. Emerging neurodegenerative evidence shows abundant somatic mutations, many with functional significance. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we sequenced PRNP in 205 sCJD cases and 160 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate somatic mutation in focal initiation of prion formation, and examined visual cortex, frontal cortex, and cerebellum. We performed multiple independent primer PCR sequencing (MIPP-seq) with an average depth of ~8,000X across PRNP and identified variants using MosaicHunter. We were able to detect variants in bulk DNA at an allele fraction as low as 0.1%. Using stringent criteria, we identified somatic variants among individuals in our cohort, but did not observe increased somatic burden in sCJD compared to controls, suggesting that somatic mutations in PRNP may not play a major role in sCJD.
Creutzfeldt-Jakob Disease (CJD) is a brain disorder linked to the PRNP gene. While the causes of some cases are known, the causes of most cases (~85%) remain a mystery. One potential factor could be changes occurring within PRNP after birth, known as somatic mutations. These mutations have been implicated in similar brain-related aging diseases. To explore the role of somatic mutations in CJD, we investigated the PRNP gene for these changes in the brains of 205 individuals with CJD and 160 individuals without the disease. Additionally, we focused on a subset of CJD patients with visual symptoms, a form of the disease known as Heidenhain variant CJD (H-sCJD). Employing a highly detailed analysis, we identified the presence of somatic mutations, even at very low levels. Surprisingly, we did not observe an increased occurrence of somatic mutations in individuals with CJD compared to those without the disease, indicating that somatic mutations likely have a minor influence in CJD.