Abstract
We previously produced a transgenic mouse line designated MT-hMet30 by introducing the human mutant transthyretin (TTR) gene carrying the mouse metallothionein promoter, and showed that the presence of human variant TTR is sufficient for amyloid deposition in various tissues of these transgenic mice. However, the expression pattern of human mutant transthyretin gene in the mouse was different from that in man. To analyse pathologic processes, it is essential to establish a transgenic mouse line in which the developmental and tissue- specific expression of the human mutant TTR gene is the same as in man. Thus, we produced two additional transgenic mouse lines carrying the human mutant TTR gene containing either 0.6 kb (0.6- hMet30) or 6.0 kb (6.0-hMet30) of the upstream region. The expression levels of 6.0-hMet30 gene in the liver and serum were the same as in man and about 10 times higher than those of 0.6- hMet30 gene. In both lines amyloid deposition was observed in similar tissues to human patients except for the peripheral and autonomic nervous tissues. The amyloid deposition started earlier and was more extensive in 6.0-hMet30 than 0.6-hMet30 mice, suggesting that the serum levels of human mutant TTR are correlated with the occurrence and degree of amyloid deposition, to some extent. Neither amyloid deposition nor degenerative changes were observed in the peripheral and autonomic nervous systems despite the transgene expression in the choroid plexus of the 6.0-hMet30 mice. In the 6.0-hMet30 mice, amyloid deposition started at 9 months of age, although the serum level of human mutant TTR reached the adult level at 1 month. These results suggest that intrinsic environmental factors other than the mutant gene are involved in the late-onset deposition of amyloid fibrils. Transgenic mice described here should be useful for analysing such factors
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References
Anderson, R. (1970) Hereditary amyloidosis with polyneuropathy. Acta Med. Scand. 188, 85-94.
Andrade, C. (1952) A peculiar form of peripheral neuropathy: familial atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75, 408-427.
Araki, S. (1986) Familial amyloidotic polyneuropathies. In Marrink, J. and Rijswijk, M.H. eds., Amyloidosis. Dordrecht: Nijhoff, pp. 195-218.
Benson, M.D. and Cohen, A.S. (1977) Generalized amyloid in a family of Swedish origin - a study of 426 family members in seven generations of a new kinship with neuropathy, nephropathy and central nervous system involvement. Ann. Intern. Med. 86, 419-24.
Benson, M.D. and F.E. Dwulet. (1986) Familial amyloidotic polyneuropathy Type 1: characterization of the prealbumin amyloid subunit and precursor protein. In Glenner, G.G., Osserman, E.F., Benditt, E.P., Caldins, E., Cohen, A.S. and Franklin, D.Z. eds., Amyloidosis, New York: Plenum Press. pp. 367-373.
Carvalho, J., Coimbra, A. and Andrade, C. (1976) Peripheral nerve fibre changes in asymptomatic children of patients with familial amyloid neuropathy. Brain 991-10.
Coimbra, A. and Andrade, C. (1971) Familial amyloid poluneuropathy: an electron microscopic study of the peripheral nerve in five cases. I. Interstitial changes. Brain 94, 199-206.
Colon, W. and Kelly, J.W. (1992) Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654-60.
Dwulet, F.E. and Benson, M.D. (1984) Primary structure of an amyloid prealbumin and its plasma precursor in a heredo-familial polyneuropathy of Swedish origin. Proc. Natl Acad. Sci. USA. 81, 694-8.
Haltia, M., Prelli, F., Ghiso, J., Kiuru, S., Somer, H., Palo, J. and Frangione, B. (1990) Amyloid protein in familial amyloidosis (Finnish type) is homologous to gelsolin, an actin-binding protein. Biochem. Biophys. Res. Comm. 167, 927-32.
Harats, N., Worth, R.O. and Benson, M.D. (1990) Evidence against early amyloid deposition in hereditary amyloidosis. In Costa, P.P., Freitas, A.F. and Saraiva, M.J.M., ed., Familial Amyloidotic Polyneuropathy and Other Transthyretin Related Disorders, Portugal: Arquivos de Medicina, pp. 251-54.
Holmgren, G., Bergstrom, S., Drugge, U., Lundgren, E. Nording-Sikstrom, C., Sandgren, O. and Steen, L. (1992) Homozygosity for the transthyretin-Met30-gene in seven individuals with familial amyloidosis with polyneuropathy detected by restriction enzyme analysis of amplified genomic DNA sequences. Clin. Genet. 41, 39-41.
Holmgren, G., Lundgren, E., Kangawa, K., Kurihara, T., Matsukura, S., Matsuo, H., Nakazato, M. and Steen, L. (1993) Diagnostic radioimmunoassay and DNA-analysis in Swedish and Japanese patients with familial amyloidotic polyneuropathy. Homozygosity for the TTR met30 gene. Acta. Neurol. Scand. 87, 124-7.
Horta, J.D.S., Filipe, I. and Duarte, S. (1964) Portugese polyneuritic familial type of amyloidosis. Pathol. Microbiol. 27, 809-25.
Ide, M., Mita, S. Ikegawa, S., Maeda, S., Shimada, K. and Araki, S. (1986) Identification of carriers of mutant prealbumin gene associated with familial amyloidotic polyneuropathy type I by Southern blot procedures: study of six pedigrees in the Arao district of Japan. Hum. Genet. 73, 281-5.
Ikeda, S., Nakano, T., Yanagisawa, N., Nakazato, M. and Tsukagoshi, H. (1992) Asymptomatic homozygous gene carrier in a family with type I familial amyloid polyneuropathy. Eur. Neurol 32, 308-13.
Jenne, D.E., Dezel, K., Blatzinger, P., Winter, P., Obermaier, B., Linke, R.P. and Atland, K. (1996) A new issoleucine substitution of Val-20 in tranthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis. Proc. Natl Acad. Sci. USA 93, 6302-7.
Krucke, W. (1963) Zur pathologishen anatomie der paramyloidose. Acta Neuropath. Suppl. II, 74-93.
Maury, C.P.J., Alli, K. and Baumann, M. (1990) Finnish hereditary amyloidosis. Febs Lett. 260, 85-7.
Mita, S., Maeda, S., Ide, M., Tsuzuki, T., Shimada, K. and Araki, S. (1986) Familial amyloidotic polyneuropathy diagnosed by cloned human prealbumin cDNA. Neurology 36, 298-301.
Nagata, Y., Tashiro, F., Murakami, T., Maeda, S., Takahashi, K., Shimada, K., Okamura, H. and Yamamura, K. (1995) The 6 kb upstream region of human transthyretin gene can direct developmental, tissue-specific and quantitatively normal expression in transgenic mouse. J. Biochem. 117, 169-75.
Nichols, W.C., Dwulet, F.E., Lepnieks, J. and Benson, M.D. (1988) Variant apolipoprotein Al as a major constituent of a human hereditary amyloid. Biochem. Biophys. Res. Commun. 156, 762-8.
Sandgren, O., Holmgren, G. and Lundgren E. (1990) Vitreous amyloidosis associated with homozygosity for the transthyretin methionine-30 gene. Arch. Ophthalmol. 108, 1584-6.
Sasaki, H., Yoshioka, N., Takagi, Y. and Sakaki, Y. (1985) Structure of the chromosomal gene for human serum prealbumin. Gene 37, 191-7.
Shimada, K., Maeda, S., Murakami, T., Nishiguchi, S., Tashiro, F., Yi, S., Wakasugi, S., Takahishi, K. and Yamamura, K. (1989) Transgenic mouse model of familial amyloidotic polyneuropathy. Mol. Biol. Med. 6, 333-43.
Silva Horta, J.D.A. and Trincao, R. (1963) Anatomie pathologique de la paramyloidose de “type portugais”. Acta Neuropath. Suppl. II, 54-65.
Takahashi, K., Yi, S., Kimura, Y. and Araki, S. (1991) Familial amyloidotic polyneuropathy type 1 in Kumamoto, Japan: a clinicopathologic, histochemical, immunohistochemical, and ultrastructural study. Hum. Pathol. 22, 519-27.
Tawara, S., Nakazato, M., Kangawa, K., Mathuo, H. and Araki, S. (1983) Identification of amyloid prealbumin variant in familial amyloidotic polyneuropathy (Japanese type). Biochem. Biophys. Res. Commun. 116, 880-8.
Teng, M.H. and Buxbaum, J.N. (1996) Transgenic mice in amyloid research: an interpretive review. Amyloid Int. Exp. Clin. Invest. 3, 187-208.
Tsuzuki, T., Mita, S., Maeda, S., Araki, S. and Shimada, K. (1985) Structure of the human prealbumin gene. J. Biol. Chem. 260, 12224-27.
Wakasugi, S., Inomoto, T., Yi, S., Naito, M., Uehira, M., Iwanaga, T., Maeda, S., Araki, K., Miyazaki, J., Takahashi, K., Shimada, K. and Yamamura, K. (1987) A transgenic mouse model of familial amyloidotic polyneuropathy. Proc. Japan. Acad. 63, 344-7.
Wright, J.R. (1977) Potassium permanganate in amyloidosis. Lab. Invest. 36, 274-81.
Yamamura, K., Wakasugi, S., Maeda, S., Inomoto, T., Iwanaga, T., Uehira, M., Araki, K., Miyazaki, J. and Shimada, K. (1987). Tissue-specific and developmental expression of human transthyretin gene in transgenic mice. Dev. Genet. 8, 195-205.
Yi, S., Takahashi, K., Naito, M., Tashiro, F., Wakasugi, S., Maeda, S., Shimada, K., Yamamura, K. and Araki, S. (1991) Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene. Am. J. Pathol. 138, 403-12.
Yoshinaga, T., Nakazato, M., Ikeda, S. and Ohnishi, A. (1992) Homozygosity for the transthyretin-Met30 gene in three Japanese siblings with type I familial amyloidotic polyneuropathy. Neurology 42, 2045-7.
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Takaoka, Y., Tashiro, F., Yi, S. et al. Comparison of amyloid deposition in two lines of transgenic mouse that model familial amyloidotic polyneuropathy, type I. Transgenic Res 6, 261–269 (1997). https://doi.org/10.1023/A:1018454527309
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DOI: https://doi.org/10.1023/A:1018454527309