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Large Exome Study Finds Inherited Prion Mutations Are More Common Than Thought, But Less Penetrant

ARTICLE IN BRIEF

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Preliminary data indicate that inherited mutations of the prion protein gene are not only far more widespread than previously thought, but also that only a few of these are highly penetrant and have the capacity to develop into full-fledged neurodegenerative disease.

Genetic researchers have reported preliminary data indicating that inherited mutations of the prion protein (PRNP) gene are not only far more widespread than previously thought, but also that only a few of these are highly penetrant and have the capacity to develop into full-fledged neurodegenerative disease. Moreover, it might be possible someday to use pharmaceutical approaches to limit the amount of the prion protein released in affected individuals, according to the January 20 report in Science Translational Medicine.

The research, which was coordinated at the MacArthur Lab at Massachusetts General Hospital, the Broad Institute of Harvard, and the Massachusetts Institute Technology (MIT), was spearheaded by a PhD student at the Broad Institute and the Biological and Biomedical Sciences Division at Harvard University

Eric Vallabh Minikel was a software engineer and data analyst at MIT when his wife, Sonia Vallabh, PhD, tested positive for the mutant D178N cis 129M allele of PRNP. The same mutation caused her mother's death in 2010, and the two dedicated themselves to studying prion mutations. The specific variant is highly penetrant, with symptoms typically occurring at around 50 years of age.

The massive study involved a large number of collaborators, notably members of the Exome Aggregation Consortium, a coalition of investigators seeking to aggregate and harmonize exome sequencing data from a wide variety of large-scale sequencing projects. Its data set includes 60,706 unrelated individuals sequenced as part of various disease-specific and population genetic studies.

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DR. JAMES MASTRIANNI: “Although, only a handful of mutations of the PRNP are clearly causal, based on linkage analysis, there are well over 30 rare mutations of PRNP that have been associated with disease and are often considered causal, but family history is either lacking or spotty. Some mutations even appear to be age-dependent, often appearing in patients who develop CJD late in life.”

To determine the possible prevalence of known PRNP mutations in the general population, the researchers also examined data on 531,575 individuals provided by the direct-to-consumer genotypic service 23andMe. The investigators excluded data from individuals from families with known prion disease. The entire data set included 16,025 prion disease cases, 60,706 population control exomes, and those provided by 23andMe.

They found that the frequency of reportedly pathogenic PRNP variants was more than 30 times higher in controls than expected on the basis of disease incidence.

“A total of 65 percent of cases underwent PRNP open reading frame sequencing, with 12 percent of all cases, or 18 percent, having a rare variant, which is consistent with an oft-cited estimate that 15 percent of cases of Creutzfeldt-Jakob disease are familial,” said Minikel.

The research team reported that no more than about 29 individuals per million in the general population should harbor the most active high-penetrance prion disease–causing variants, and that about 17 cases in the ExAC database and 15 people in 23andMe data would have been expected to harbor such variants.

“Instead, we found that variants in PRNP occupy a broad spectrum, but with big differences in how bad they are,” Minikel told Neurology Today. “Variants previously considered rare are actually pretty common in the general populations, yet the patients who have been told they have a PNRP mutation, and their lifetime risk of disease is 100 percent, may only have 1 percent or less risk.”

Significantly, they found that three healthy older persons had just one non-functional prion gene allele and, unlike those with two, it means they likely had only half the normal amount of cellular prion protein, providing the first human genetic data on the effects of a 50 percent reduction in the degree of impact in such individuals. No one has identified persons before with only one functional PRNP gene, which means, in theory that it might be possible to safely reduce PRNP gene expression by 50 percent in other prion disease patients.

“For the first time this should answer the question of whether therapeutic agents to reduce PRNP expression may not only be effective, but that patients with penetrant variations might be treated safely – something that will require additional research,” said Minikel.

BROADER IMPLICATIONS POSSIBLE

The researchers found that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence, and while some of this excess can be attributed to benign variants falsely assigned as pathogenic, others have genuine effects on disease susceptibility. In all, PRNP variants confer an estimated lifetime risks ranging from less than 1 percent to 100 percent, depending on the type and site of the mutation.

The team looked specifically at missense variations which occur when a change in a single nucleotide encodes for an abnormal protein, in this case PRNP.

The probability that a carrier of a suspected disease-causing genotype will develop disease has generally been, and continues to be uncharted territory, said Minikel, but researchers are increasingly developing a better understanding of penetrance.

“Although the number of individuals and the depth of available phenotype data were limited, and the lifetime inactivation of a gene is an imperfect model of the effects of pharmacological depletion of the gene product, the data provide preliminary evidence that a reduction in PRNP dosage, if achievable in patients, is likely to be tolerated,” said Minikel.

In the general population, of all persons with these variants, most will not develop prion disease and only one half of individuals with a family member who develop disease have penetrant versions.

“For most individuals there is only a very small risk, however there are those with much higher risk,” he noted.

Increasingly large exome sequencing data sets will soon enable researchers to test whether the same is true of other genes currently being targeted in substrate-reduction therapeutic approaches for other protein-misfolding disorders, he continued.

“Together, our findings highlight the value of large reference data sets of human genetic variation for informing both genetic counseling and therapeutic strategy. I hope that what we have done might be possible with other genetic dominant neurodegenerative diseases, and that we will see more efforts like this,” Minkel told Neurology Today.

“We did not predict that we would discover these findings because all PRNP variants were thought to convey pathogenic risk. For 10 years or so, researchers have been investigating ways to address PRNP using small molecules to counter expression of PRNP and tests in mice gave shown they can reduce protein levels, which is also promising. As exome data sets increase, we will get more information about PRNP phenotypes and penetrance.”

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ERIC V. MINIKEL: “Variants previously considered rare are actually pretty common in the general populations, yet the patients who have been told they have a PNRP mutation, and their lifetime risk of disease is 100 percent, may only have 1 percent or less risk.”

EXPERTS COMMENT

James Mastrianni, MD, PhD, an associate professor of neurology and director of the Center for Comprehensive Care & Research on Memory Disorders at the University of Chicago, told Neurology Today that the findings are important for several reasons.

“The paper highlights a key problem associated with genetic studies of rare disorders like prion disease,” said Dr. Mastrianni, the Helen McLoraine Neuroscientist at the Brain Research Foundation, a public, nonprofit, charitable organization that provides funding for investigators.

“Although, only a handful of mutations of the PRNP are clearly causal, based on linkage analysis, there are well over 30 rare mutations of PRNP that have been associated with disease and are often considered causal, but family history is either lacking or spotty. Some mutations even appear to be age-dependent, often appearing in patients who develop CJD late in life.”

He said that Minikel and his colleagues took advantage of newly available large genetic databases and found a much higher prevalence of some mutations in control populations that would be expected in such a rare disease.

“They then assigned some much needed lifetime risk numbers, which could be valuable in genetic counseling. The study is an important reminder to those in the field that caution is advised about casually assigning cause to a genetic variant of a rare disease,” he stated.

“The investigators' incidental recognition of a few asymptomatic individuals with heterozygous loss-of-function due to PRNP variants also gives hope to those of us who are applying RNA interference to knock down expression of the mutates allele as a potential therapy for genetic prion disease.”

LINK UP FOR MORE INFORMATION:

•. Minikel EV, Vallabh SM, Lek M, et al. Quantifying prion disease penetrance using large population control cohorts http://stm.sciencemag.org/content/8/322/322ra9. Sci Transl Med 2016:8:322ra9.
    •. Prusiner SB, Woerman AL, Mordes DA, et al. Evidence for {alpha}-synuclein prions causing multiple system atrophy in humans with parkinsonism http://www.pnas.org/content/112/38/E5308.abstract. PNAS 2015:112:E5308–E5317.
      •. Jansen C, Parchi P, Capellari S, et al. Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP http://link.springer.com/article/10.1007%2Fs00401-009-0609-x. Acta Neuropathol 2010;119:189–197.
        •. Muñoz-Nieto M, Ramonet N, López-Gastón NJI, et al. A novel mutation I215V in the PRNP gene associated with Creutzfeldt–Jakob and Alzheimer's diseases in three patients with divergent clinical phenotypes http://www.ncbi.nlm.nih.gov/pubmed/22763467. J Neurol 2013;260:77–84.
          •. Bütefisch CM, Gambetti P, Cervenakova L, et al. Inherited prion encephalopathy associated with the novel PRNP H187R mutation: A clinical study http://www.neurology.org/content/55/4/517.short. Neurology 2000:55:517–522.