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Dissecting pathophysiology of a human dominantly inherited disease, familial amyloidotic polyneuropathy, by using genetically engineered mice
doi: 10.2478/fzm-2022-0009
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Abstract: Familial amyloidotic polyneuropathy (FAP) is a type of systemic amyloidosis characterized by peripheral and autonomic neuropathy. Although FAP is a typical autosomal dominant disorder caused by a point mutation in the TTR gene, the average age at onset varies significantly among different countries. This discrepancy clearly suggests that a combination of intrinsic factors as well as extrinsic (environmental) factors shapes the development of FAP. However, these factors are difficult to analyze in humans, because detailed pathologic tissue analysis is only possible at autopsy. Thus, mouse models have been produced and used to disentangle these factors. This review covers the mouse models produced thus far and how these models are applied to analyze intrinsic and extrinsic factors involved in disease development and to test drug efficacy.
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Figure 1. Relationship between the concentration of hTTR homotetramer and the amount of amyloid deposition
Concentrations of hTTR homotetramer were estimated from the amounts of TTR mRNA and the serum hTTR concentrations. Amounts of amyloid deposition were correlated with the concentration of the hTTR homotetramer.
Figure 2. Effect of intestinal flora on amyloid deposition
The 6.0-hM30 mice were kept under SPF or CV conditions. Amyloid deposition was observed only in mice maintained under CV conditions. Under SPF conditions, the intestinal flora remained fairly constant, and the major flora was group Ⅰ symbiotes, such as gram-positive anaerobic cocci. In contrast, under CV conditions, the group Ⅲ weak pathogens such as yeast, staphylococci, and Pseudomonas, increased, while that of group Ⅰ symbiotes decreased. GPAC, gram positive anaerobic cocci; GPAR, gram positive anaerobic rods.
Figure 3. Role of Cys10 in amyloid deposition
Three recombinant cDNAs encoding normal hTTRC10:V30, hTTRC10:M30, and hTTRSer10:Met30 were introduced into the cDNA cloning site of the plasmid pTG.27; the resultant plasmids were designated 7.2-hC10:V30c, 7.2-hC10:M30c, and 7.2-hS10:M30c, respectively. Amyloid deposition was observed only in 7.2-hC10:M30c mice.
Table 1. Serum TTR concentrations and amounts of amyloid deposition
Author Mouse Frequency of amyloid deposition Construct Ttr Serum conc. up tp 5 months 6 – 11 months 12 – 17 months 18 – 24 months Kohno 1997[31] 6.0-hTTRV30M +/+ 30 – 65 μg/mL not done 1/6 2/6 4/6 6.0-hTTRV30M −/− 22 – 79 μg/mL not done 3/6 2/6 3/6 Takaoka 2004[19] 7.2-hTTRV30 +/+ 38 – 53 μg/mL not done 0/1 0/8 0/27 7.2-hTTRC10:V30M +/+ 48 – 57 μg/mL not done 0/4 0/19 14/27 7.2-hTTRC10S: V30M +/+ 4 – 78 μg/mL not done 0/4 0/11 0/40 Inoue 2008[30] 0.6-hTTRV30M +/+ 15 – 30 μg/mL not done 0/2 4/8 4/6 6.0-hTTRV30M +/+ 137 – 145 μg/mL not done 0/12 7/11 6/6 MT-hTTRV30M +/+ 10 – 48 μg/mL not done 1/8 10/13 7/7 Teng 2001[21] 19.2kb hTTRV30 +/+ 1000 – 3500 μg/mL not done not done 0/15 13/83 19.2kb hTTRL55P +/+ 10 – 30 μg/mL not done not done 0 0 Sousa 2002[29] MT-hTTRL55P −/− 50 – 200 μg/mL 0/21 0/12 0/11 0/11 6.0-hTTRV30M +/+ not done 0/24 0/25 0/25 1/25 Ttr−/− : 6.0-hTTRV30M −/− not done 1/1 0/2 13/13 16/16 Li 2018[80] Ttr+/+ : 6.0-hTTRV30M +/+ 142 – 149 μg/mL not done 8/10 6/7 12/12 Ttr−/− : 6.0-hTTRV30M −/− 131 – 143 μg/mL not done 5/10 5/7 12/12 TtrV30/V30: Rbp4RBP4 −/− 6.0 – 6.6 μg/mL not done 10/10 7/8 12/12 TtrV30/M30: Rbp4RBP4 −/− 5.5 – 5.9 μg/mL not done 0/10 6/6 8/8 The amounts of amyloid deposition varied greatly depending on housing conditions, type of mutation, etc. For example, Sousa et al. reported that amyloid deposition was observed only one out of 25 mice, while we reported that amyloid deposition was observed most of mice even though both groups used the same 6.0-hTTRV30M. 
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Table 2. Amyloid deposition in various Tg Lines
Tg Lines Tissue 6 months 12 months 18 months 24 months 0.6-hMet30 heart − − − ~ + − small intestine − − + ~ + + − ~ + kidney − − − − skin − − − ~ + − sciatic nerve − − − − 6.0-hMet30 heart − − ~ + − + ~ + + + small intestine − − ~ + + − ~ + + + kidney − − ~ ± − + + + skin − − ~ + − − ~ + sciatic nerve − − − − MT-hMet30 heart − − ~ + + ~ + + + + + small intestine − ~ + − ~ + + + + + + + + kidney − − ~ + + + ~ + + + + + + skin − + + + + sciatic nerve − − − − Amyloid deposition in 6.0-h Met30 was earlier than that in 0.6-h Met30. This was expected from the data that serum TTR level was higher in 6.0-h Met30 than in 0.6-h Met30 line. However, amyloid deposition in MT-h Met30 was earlier and larger than those in other lines.
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