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Association of a null allele of SPRN with variant Creutzfeldt-Jakob Disease
  1. Jonathan A Beck (j.beck{at}prion.ucl.ac.uk)
  1. MRC Prion Unit, United Kingdom
    1. Tracy Campbell (t.campbell{at}prion.ucl.ac.uk)
    1. MRC Prion Unit, United Kingdom
      1. Gary Adamson (g.adamson{at}prion.ucl.ac.uk)
      1. MRC Prion Unit, United Kingdom
        1. Mark Poulter (m.poulter{at}prion.ucl.ac.uk)
        1. MRC Prion Unit, United Kingdom
          1. James Uphill (j.uphill{at}prion.ucl.ac.uk)
          1. MRC Prion Unit, United Kingdom
            1. Eleni Molou (e.molou{at}prion.ucl.ac.uk)
            1. MRC Prion Unit, United Kingdom
              1. John Collinge (j.collinge{at}prion.ucl.ac.uk)
              1. MRC Prion Unit, United Kingdom
                1. Simon Mead (s.mead{at}prion.ucl.ac.uk)
                1. MRC Prion Unit, United Kingdom

                  Abstract

                  Despite clear evidence from mouse linkage studies of multiple genetic loci affecting incubation periods of prion disease[1;2], no specific human genes have been identified aside from the prion protein gene (PRNP). A recently characterised highly conserved gene, SPRN, encodes Shadoo (Sho, shadow of prion protein) which has protein homology and possible functional links with the prion protein[3]. We carried out a genetic screen of the open reading frame of SPRN by direct sequencing in 522 prion disease patients, including 107 with variant Creutzfeldt-Jakob disease (vCJD), and 861 healthy controls. We identified a common coding variant of SPRN, two further single nucleotide polymorphisms (SNPs) and three rare insertion or deletion variants. A single base pair insertion at codon 46, predicted to cause a frameshift and potentially a novel protein, was found in two vCJD patients but not controls (P = 0.01). Two linked SNPs, one in intron 1 the other a missense variant at codon 7, were associated with risk of sporadic CJD (P=0.009). These data justify the functional genetic characterisation of SPRN and support the involvement of Shadoo in prion pathobiology.

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