title: Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy.
abstract: Amyloid fibrils derived from the Japanese, Portuguese, and Swedish types of familial amyloidotic polyneuropathy all consist of a variant transthyretin (TTR) with a substitution of methionine for valine at position 30 (TTR Met 30). In an attempt to establish an animal model of TTR Met-30-associated homozygous familial amyloidotic polyneuropathy and to study the structural and functional properties of human TTR Met 30, we generated a mouse line carrying a null mutation at the endogenous ttr locus (ttr-/-) and the human mutant ttr gene (6.0-hMet 30) as a transgene. In these mice, human TTR Met-30-derived amyloid deposits were first observed in the esophagus and stomach when the mice were 11 months of age. With advancing age, amyloid deposits extended to various other tissues. Because no significant difference was detected in the onset, progression, and tissue distribution of amyloid deposition between the ttr-/- and ttr+/+ transgenic mice expressing 6.0-hMet 30, endogenous normal mouse TTR probably does not affect the deposition of human TTR Met-30-derived amyloid in mice. TTR is a tetramer composed of four identical subunits that binds thyroxine (T4) and plasma retinol-binding protein. The introduction of 6.0-hMet 30 into the ttr-/- mice significantly increased their depressed serum levels of T4 and retinol-binding protein, suggesting that human TTR Met 30 binds T4 and retinol-binding protein in vivo. The T4-binding ability of human TTR Met 30 was confirmed by the analysis of T4-binding proteins in the sera of ttr-/- transgenic mice expressing 6.0-hMet 30. The T4-binding studies also demonstrated the presence of hybrid tetramers between mouse and human TTR subunits in the ttr+/+ transgenic mice expressing 6.0-hMet 30.
authors.affiliation: Department of Biochemistry, Yamanashi Medical University, Yamanashi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kohno
authors.forename: J A
authors.initials: JA
authors.lastname: Palha
authors.forename: K
authors.initials: K
authors.lastname: Miyakawa
authors.forename: M J
authors.initials: MJ
authors.lastname: Saraiva
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.forename: T
authors.initials: T
authors.lastname: Mabuchi
authors.forename: W S
authors.initials: WS
authors.lastname: Blaner
authors.forename: H
authors.initials: H
authors.lastname: Iijima
authors.forename: S
authors.initials: S
authors.lastname: Tsukahara
authors.forename: V
authors.initials: V
authors.lastname: Episkopou
authors.forename: M E
authors.initials: ME
authors.lastname: Gottesman
authors.forename: K
authors.initials: K
authors.lastname: Shimada
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Yamamura
authors.forename: S
authors.initials: S
authors.lastname: Maeda
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D017772:Amyloid Neuropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011228:Prealbumin / Q000235:genetics; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry; D012177:Retinol-Binding Proteins / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma; D013974:Thyroxine / Q000097:blood
chemical_list: D000682:Amyloid; D001798:Blood Proteins; D011228:Prealbumin; D011993:Recombinant Fusion Proteins; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D013974:Thyroxine