Linkage of a Prion Protein Missense Variant to Gerstmann-Straussler Syndrome
K. Hsiao, H.F. Baker, T.J. Crow, M. Poulter, F. Owen,
J.D. Terwilliger, D. Westaway, J. Ott, S.B. Prusiner
Nature , 338(6213), 342--345 (1989 Mar 23)
Abstract
Gerstmann-Straussler syndrome is a rare familial neurodegenerative
condition that is vertically transmitted, in an apparently autosomal
dominant way. It can also be horizontally transmitted to non-human
primates and rodents through intracerebral inoculation of brain
homogenates from patients with the disease. The exact incidence of
the syndrome is unknown but is estimated to be between one and ten
per hundred million. Patients initially suffer from ataxia or
dementia and deteriorate until they die, in one to ten years.
Protease-resistant prion protein (PrP) and PrP-immunoreactive
amyloid plaques with characteristic morphology accumulate in the
brains of these patients. Current diagnostic criteria for
Gerstmann-Straussler syndrome incorporate clinical and
neuropathological features, as animal transmission studies can be
unreliable. PrP is implicated in the pathogenesis and transmission
of the condition and in scrapie, an equivalent animal disease. It
was discovered by enriching scrapie-infected hamster brain fractions
for infectivity. Because there is compelling evidence that the
scrapie isoform of PrP is a necessary component of the infectious
particle, it seemed possible that the PrP gene on the short arm of
human chromosome 20 in Gerstmann-Straussler syndrome might be
abnormal. We show here that PrP codon 102 is linked to the putative
gene for the syndrome in two pedigrees, providing the best evidence
to date that this familial condition is inherited despite also being
infectious, and that substitution of leucine for proline at PrP
codon 102 may lead to the development of Gerstmann-Straussler syndrome.
