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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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Sequence analysis of PRNP in three patients with prion diseases.The coding region was sequenced using fluorescence-labeled primers on an automated sequencing system (LI-COR, Lincoln, Neb.). Short fragments of PRNP of (A) a patient with the normal codon 188, (B) patient A with the T188R mutation and (C) patient B with the T188K mutation are shown using a primer for the sequencing that reads the antisense strand.
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pone-0002147-g001: Sequence analysis of PRNP in three patients with prion diseases.The coding region was sequenced using fluorescence-labeled primers on an automated sequencing system (LI-COR, Lincoln, Neb.). Short fragments of PRNP of (A) a patient with the normal codon 188, (B) patient A with the T188R mutation and (C) patient B with the T188K mutation are shown using a primer for the sequencing that reads the antisense strand.

Mentions: The analysis of the coding region of PRNP showed an abnormal pattern in the SSCP analysis compared to the normal PRNP of patients without sequence aberrations and to PRNP of patients with various known mutations. Sequencing revealed a cytosine to guanine transversion at the second position at codon 188 on one allele resulting in an amino acid exchange of threonine (ACG) to arginine (AGG) (T188R) (Figure 1B). The amino acid at codon 129 was valine (V) at both alleles.


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)

Sequence analysis of PRNP in three patients with prion diseases.The coding region was sequenced using fluorescence-labeled primers on an automated sequencing system (LI-COR, Lincoln, Neb.). Short fragments of PRNP of (A) a patient with the normal codon 188, (B) patient A with the T188R mutation and (C) patient B with the T188K mutation are shown using a primer for the sequencing that reads the antisense strand.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002147-g001: Sequence analysis of PRNP in three patients with prion diseases.The coding region was sequenced using fluorescence-labeled primers on an automated sequencing system (LI-COR, Lincoln, Neb.). Short fragments of PRNP of (A) a patient with the normal codon 188, (B) patient A with the T188R mutation and (C) patient B with the T188K mutation are shown using a primer for the sequencing that reads the antisense strand.
Mentions: The analysis of the coding region of PRNP showed an abnormal pattern in the SSCP analysis compared to the normal PRNP of patients without sequence aberrations and to PRNP of patients with various known mutations. Sequencing revealed a cytosine to guanine transversion at the second position at codon 188 on one allele resulting in an amino acid exchange of threonine (ACG) to arginine (AGG) (T188R) (Figure 1B). The amino acid at codon 129 was valine (V) at both alleles.

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