TY - JOUR
T1 - Genetic microheterogeneity of human transthyretin detected by IEF
AU - Altland, Klaus
AU - Benson, Merrill D.
AU - Costello, Catherine E.
AU - Ferlini, Alessandra
AU - Hazenberg, Bouke P C
AU - Hund, Ernst
AU - Kristen, Arnt V.
AU - Linke, Reinhold P.
AU - Merlini, Giampaolo
AU - Salvi, Fabrizio
AU - Saraiva, Maria J.
AU - Singer, Reinhard
AU - Skinner, Martha
AU - Winter, Pia
PY - 2007/6
Y1 - 2007/6
N2 - Mutations of the human transthyretin (TTR) gene have attracted medical interest as a cause of amyloidosis. Recently, we have described in detail an electrophoretic procedure with PAGE followed by IEF in urea gradients for the study of the microheterogeneity of TTR monomers (Altland, K., Winter, P., Sauerborn, M. K., Electrophoresis 1999,20, 1349-1364). In this paper, we present a study on 49 different mutations of TTR including 33 that result in electrically neutral amino acid substitutions. The aims of the investigation were to test the sensitivity of the procedure to detect TTR variants in patients with TTR amyloidosis and their relatives and to identify some common characteristics that could explain the amyloidogenicity of these variants. We found that all tested amyloidogenic mutations could be detected by our method with the exception of those for which the corresponding variant was absent in plasma samples. Most of the electrically neutral amyloidogenic TTR variants had in common a reduced conformational stability of monomers by the activity of protons and urea. For three variants, e.g. TTR-F64L, TTR-I107V and TTR-V122I, the monomers had a conformational stability close to that of normal monomers but we found experimental and structural arguments for a weakening of the monomer-monomer contact. All types of amyloidogenic mutations affected the stability of TTR tetramers.
AB - Mutations of the human transthyretin (TTR) gene have attracted medical interest as a cause of amyloidosis. Recently, we have described in detail an electrophoretic procedure with PAGE followed by IEF in urea gradients for the study of the microheterogeneity of TTR monomers (Altland, K., Winter, P., Sauerborn, M. K., Electrophoresis 1999,20, 1349-1364). In this paper, we present a study on 49 different mutations of TTR including 33 that result in electrically neutral amino acid substitutions. The aims of the investigation were to test the sensitivity of the procedure to detect TTR variants in patients with TTR amyloidosis and their relatives and to identify some common characteristics that could explain the amyloidogenicity of these variants. We found that all tested amyloidogenic mutations could be detected by our method with the exception of those for which the corresponding variant was absent in plasma samples. Most of the electrically neutral amyloidogenic TTR variants had in common a reduced conformational stability of monomers by the activity of protons and urea. For three variants, e.g. TTR-F64L, TTR-I107V and TTR-V122I, the monomers had a conformational stability close to that of normal monomers but we found experimental and structural arguments for a weakening of the monomer-monomer contact. All types of amyloidogenic mutations affected the stability of TTR tetramers.
KW - Amyloidosis
KW - Familial amyloidotic polyneuropathy
KW - Microheterogeneity
KW - Transthyretin
KW - Urea titration curve
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U2 - 10.1002/elps.200600840
DO - 10.1002/elps.200600840
M3 - Article
C2 - 17503405
AN - SCOPUS:34447271771
VL - 28
SP - 2053
EP - 2064
JO - Electrophoresis
JF - Electrophoresis
SN - 0173-0835
IS - 12
ER -