title: Aged vervet monkeys developing transthyretin amyloidosis with the human disease-causing Ile122 allele: a valid pathological model of the human disease.
abstract: Mutant forms of transthyretin (TTR) cause the most common type of autosomal-dominant hereditary systemic amyloidosis. In addition, wild-type TTR causes senile systemic amyloidosis, a sporadic disease seen in the elderly. Although spontaneous development of TTR amyloidosis had not been reported in animals other than humans, we recently determined that two aged vervet monkeys (Chlorocebus pygerythrus) spontaneously developed systemic TTR amyloidosis. In this study here, we first determined that aged vervet monkeys developed TTR amyloidosis and showed cardiac dysfunction but other primates did not. We also found that vervet monkeys had the TTR Ile122 allele, which is well known as a frequent mutation-causing human TTR amyloidosis. Furthermore, we generated recombinant monkey TTRs and determined that the vervet monkey TTR had lower tetrameric stability and formed more amyloid fibrils than did cynomolgus monkey TTR, which had the Val122 allele. We thus propose that the Ile122 allele has an important role in TTR amyloidosis in the aged vervet monkey and that this monkey can serve as a valid pathological model of the human disease. Finally, from the viewpoint of molecular evolution of TTR in primates, we determined that human TTR mutations causing the leptomeningeal phenotype of TTR amyloidosis tended to occur in amino acid residues that showed no diversity throughout primate evolution. Those findings may be valuable for understanding the genotype-phenotype correlation in this inherited human disease.
authors.affiliation: Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Ueda
authors.forename: Naohide
authors.initials: N
authors.lastname: Ageyama
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakamura
authors.forename: Minami
authors.initials: M
authors.lastname: Nakamura
authors.forename: James Kenn
authors.initials: JK
authors.lastname: Chambers
authors.forename: Yohei
authors.initials: Y
authors.lastname: Misumi
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.forename: Satomi
authors.initials: S
authors.lastname: Kawahara
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tasaki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Konen
authors.initials: K
authors.lastname: Obayashi
authors.forename: Erika
authors.initials: E
authors.lastname: Sasaki
authors.forename: Yumi
authors.initials: Y
authors.lastname: Une
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D028226:Amyloidosis, Familial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002522:Chlorocebus aethiops / Q000097:blood / Q000235:genetics*; D004195:Disease Models, Animal; D006334:Heart Function Tests; D006801:Humans; D008252:Macaca fascicularis / Q000097:blood / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D011228:Prealbumin / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D011228:Prealbumin; D011994:Recombinant Proteins