Evidence for a pathogenic role of different mutations at codon 188 of PRNP

Clinical and pathological changes in familial Creutzfeldt-Jakob
disease (CJD) cases may be similar or indistinguishable from
sporadic CJD. Therefore determination of novel mutations in PRNP
remains of major importance. We identified two different rare
mutations in codon 188 of the prion protein gene (PRNP) in four
patients suffering from a disease clinically very similar to the
major subtype of sporadic CJD. Both mutations result in an exchange
of the amino acid residue threonine for a highly basic residue,
either arginine (T188R) or lysine (T188K). The T188R mutation was
found in one patient and the T188K mutation in three patients. The
prevalence of mutations at codon 188 of PRNP was tested in 593
sporadic CJD cases and 735 healthy individuals. Neither mutation
was found. The data presented here argue in favor of T188K being a
pathogenic mutation causing genetic CJD. Since one individual with
this mutation, who is the father of a clinically affected patient
with T188K mutation, is now 79 years old and shows no signs of
disease, this mutation is likely associated with a penetrance under
100%. Further observations will have to show whether T188R is a
pathogenic mutation.