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Rare structural genetic variation in human prion diseases.

Abstract：

:Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.

journal_name

Neurobiol Aging

journal_title

Neurobiology of aging

authors

Lukic A,Uphill J,Brown CA,Beck J,Poulter M,Campbell T,Adamson G,Hummerich H,Whitfield J,Ponto C,Zerr I,Lloyd SE,Collinge J,Mead S

doi

10.1016/j.neurobiolaging.2015.01.011

subject

Has Abstract

pub_date

2015-05-01 00:00:00

pages

2004.e1-8

issue

eissn

0197-4580

issn

1558-1497

pii

S0197-4580(15)00044-5

journal_volume

pub_type

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Rare structural genetic variation in human prion diseases.