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

Roeber S, Grasbon-Frodl EM, Windl O, Krebs B, Xiang W, Vollmert C, Illig T, Schröter A, Arzberger T, Weber P, Zerr I, Kretzschmar HA - PLoS ONE (2008)

Bottom Line: The T188R mutation was found in one patient and the T188K mutation in three patients.Neither mutation was found.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%.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, München, Germany.

ABSTRACT
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.

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Related in: MedlinePlus

Western blot analysis of PrP after proteinase K digestion (lanes 1–3) using mAb 3F4.Lane1: PrPSc type 1 from a sporadic CJD case. Lane 2: PrPSc type 2 from a sporadic CJD case. Lane 3: Frontal cortex of patient D. As seen in lane 3 there is an additional band migrating at an apparent MW of 17 kDa.
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pone-0002147-g003: Western blot analysis of PrP after proteinase K digestion (lanes 1–3) using mAb 3F4.Lane1: PrPSc type 1 from a sporadic CJD case. Lane 2: PrPSc type 2 from a sporadic CJD case. Lane 3: Frontal cortex of patient D. As seen in lane 3 there is an additional band migrating at an apparent MW of 17 kDa.

Mentions: The protease resistant PrP in brain homogenate from patient D was further analysed using Western blotting with the antibody 3F4. A PrPSc pattern type 1 was found (Figure 3, lane 3) similar to the type 1 pattern of sCJD case (MM1, Figure 3, lane 1). In addition there was a fragment migrating at about 17 kDa detected with the antibody 3F4. Additional bands have been reported in genetic prion diseases (mainly GSS), some also in sCJD and iCJD [19]–[22].


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

Roeber S, Grasbon-Frodl EM, Windl O, Krebs B, Xiang W, Vollmert C, Illig T, Schröter A, Arzberger T, Weber P, Zerr I, Kretzschmar HA - PLoS ONE (2008)

Western blot analysis of PrP after proteinase K digestion (lanes 1–3) using mAb 3F4.Lane1: PrPSc type 1 from a sporadic CJD case. Lane 2: PrPSc type 2 from a sporadic CJD case. Lane 3: Frontal cortex of patient D. As seen in lane 3 there is an additional band migrating at an apparent MW of 17 kDa.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2366066&req=5

pone-0002147-g003: Western blot analysis of PrP after proteinase K digestion (lanes 1–3) using mAb 3F4.Lane1: PrPSc type 1 from a sporadic CJD case. Lane 2: PrPSc type 2 from a sporadic CJD case. Lane 3: Frontal cortex of patient D. As seen in lane 3 there is an additional band migrating at an apparent MW of 17 kDa.
Mentions: The protease resistant PrP in brain homogenate from patient D was further analysed using Western blotting with the antibody 3F4. A PrPSc pattern type 1 was found (Figure 3, lane 3) similar to the type 1 pattern of sCJD case (MM1, Figure 3, lane 1). In addition there was a fragment migrating at about 17 kDa detected with the antibody 3F4. Additional bands have been reported in genetic prion diseases (mainly GSS), some also in sCJD and iCJD [19]–[22].

Bottom Line: The T188R mutation was found in one patient and the T188K mutation in three patients.Neither mutation was found.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%.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, München, Germany.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus