See also: amyloidosismutations.com
DATA BASE ON TRANSTHYRETIN MUTATIONS
Maria João Mascarenhas Saraiva Amyloid Unit. Institute of Molecular and Cellular Biology R. Campo Alegre 823; 4150 Porto PORTUGAL tel: 351-22-6074900;fax:351-22-6099157 e-mail: mjsaraiv@ibmc.up.pt http://www.ibmc.up.pt/groups/amiloide
Over 80 different mutations in transthyretin (TTR) have been reported. The vast majority is inherited in an autosomal dominant manner and is related to amyloid deposition, affecting predominantly peripheral nerve and/or the heart. A small portion of TTR mutations is apparently non-amyloidogenic. Among these, are mutants responsible for hyperthyroxinemia, presenting high affinity for thyroxine (a TTR ligand). Compound heterozygotic individuals for TTR mutants have been described; noteworthy is the clinically protective effect exerted by a non-pathogenic over a pathogenic mutation.
Transthyretin - TTR (OMIM 176300) is a well characterized molecule that consists of a tetramer of identical subunits of 127 amino acids each; the molecular structure has been determined by X-ray analysis (Blake et al. 1974). TTR is a plasma transport protein for thyroxine - T4 - and for retinol, through the association with retinol binding protein (RBP). Part of the interest in TTR stems from the occurrence of mutations in the molecule leading to the extracellular deposition in tissues as amyloid. Main sites of deposition are the peripheral nerve and/or the heart, associated with neuropathies and/or cardiomyopathies, respectively. Both are late onset autosomal dominant disorders. Identification and characterization of TTR mutations in health and disease will help to unravel the unknown pathogenic mechanisms underlying TTR amyloidosis.
Amyloidogenic TTR mutations
Familial amyloidotic polyneuropathy - FAP - was first described by Andrade in 1952 in the Northern area of Portugal; kindreds had an age of onset of clinical symptoms in the third to fourth decade of life. Early impairment of temperature and pain sensation in the feet and autonomic dysfunction leading to paresis, malabsorption, sphincter dysfunction, electrocardiographic abnormalities, emaciation and death were typical clinical features. The genetic defect in these Portuguese FAP kindreds was ascribed to a valine for methionine substitution at position 30 (Saraiva et al. 1984) resulting from a single A for G nucleotide change (Sasaki et al. 1984). Over 500 kindreds have been identified in Portugal, constituting the largest focus of FAP worldwide; the patient prevalence rate in the area where FAP is common in Portugal has been estimated as 105x10 -5 (Sousa et al. 1995), and the gene carrier frequency as 1 in 625 (Alves et al. 1997). The second largest known Val30Met focus is Northern Sweden where more that 350 families have been diagnosed (Holmgren et al. 1994); other relevant foci include Japan and the Island of Maiorca (Araki 1984; Munar-Qués et al. 1997). A few cases of homozygosity for the Met 30 gene occur but do not lead to a more severe form of the disease (Holmgren et al. 1988).
Many other TTR mutations associated with FAP clinically not differing from the original description by Andrade have been described; others, give rise to variable phenotypes such as the presence of both neuropathy and cardiomyopathy, presentation of carpal tunnel syndrome, predominant vitreous TTR deposition and leptomeningeal involvement. A few TTR mutations are related to cardiomyopathy without neurological symptoms. The most common TTR mutation associated with cardiac amyloidosis is Val122Ile, described in the Black population; after the age of 60, isolated cardiac amyloidosis is four times more common among blacks than whites in the United States and 3.9 percent of blacks are heterozygous for Val122Ile; a few cases of homozygosity for this mutant have been found (Jacobson et al., 1997).
Table 1 shows single point mutations (over 100) and one deletion identified in TTR amyloidosis.
Table 1 - Transthyretin Amyloidoses
| Mutation | Codon change | Predominant | Origin | Reference |
| Clinical Features | ||||
| Cys10Arg | TGT CGT | PN, AN, Eye | Hungary | Uemichi et al. (1992) |
| Leu12Pro | CTG CCG | LM, PN, AN | UK | Brett et al. (1999) |
| Asp18Glu | GAT GAG | PN, AN | Columbia | Booth et al. (1996) |
| Asp18Gly | GAT GGT | LM | Hungary | Vidal et al. (1996) |
| Asp18Asn | GAT AAT | Heart | USA | Connors et al. (2001) |
| Val20Ile | GTC ATC | Heart | Germany | Jenne et al. (1996) |
| Ser23Asn | AGT AAT | Heart | Portugal | Connors et al. (1999) |
| Pro24Ser | CCT TCT | Heart, CTS, PN | USA | Uemichi et al. (1995) |
| Ala25Thr | GCC ACC | LM,PN | Japan | Ikeda et al. (2003) |
| Ala25Ser | GCC TCC | Heart, PN | USA | Yazaki et al., (2002) |
| Val28Met | GTG ATG | PN, AN | Portugal | Carvalho et al. (2000) |
| Val30Met | GTG ATG | PN, AN, Eye | several | several |
| Val30Ala | GTG GCG | Heart, AN | Germany | Jones et al. (1992) |
| Val30Leu | GTG CTG | PN, AN | Japan | Nakazato et al. (1992) |
| Val30Gly | GTG GGG | LM, Eye | France | Petersen et al. (1997) |
| Val32Ala | GTG GCG | PN, AN | China | Pica et al.(2005) |
| Phe33Ile | TTC ATC | PN, Eye | Poland | Nakazato et al. (1984) |
| Phe33Leu | TTC CTC | PN, AN | Poland | Ii et al. (1991) |
| Phe33Val | TTC GTC | PN, AN | UK | Booth et al. (1996) |
| Phe33Cys | TTC TGC | CTS, Heart | USA | Lim et al. (2003) |
| Arg34Thr | AGA ACA | PN, Heart | Italy | Patrosso et al. (1998) |
| Arg34Gly | AGA GGA | Eye | UK | |
| Lys35Asn | AAG AAC | PN, AN, Heart | France | Reilly et al. (1995) |
| Lys 35 Thr | AAG ACG | Eye | USA | |
| Ala36Pro | GCT CCT | PN, Eye | Greece | Jones et al. (1991) |
| Asp38Ala | GAT GCT | PN, Heart | Japan | Kishikawa et al. (1999) |
| Asp38Val | GAT GTT | Heart, PN | Spain | Augustin et al.(2007) |
| Trp41Leu | TGG TTG | Eye | Russia | Yazaki et al. (2002a) |
| Glu42Gly | GAG GGG | PN, AN | Japan | Ueno et al. (1990) |
| Glu42Asp | GAG GAT | Heart | France | Dupuy et al. (1998) |
| Phe44Ser | TTT TCT | PN, AN, Heart | Ireland | Klein et al. (1998) |
| Ala45Asp | GCC GAC | Heart | Italy | Jacobson et al. (1993) |
| Ala45Ser | GCC UCC | Heart | Sweden | Janunger et al. (2000) |
| Ala45Thr | GCC ACC | Heart | Italy | Saraiva et al. (1992) |
| Gly47Arg | GGG CGG | PN, AN | Japan | Murakami et al. (1992) |
| Gly47Ala | GGG GCG | Heart, PN, AN | Italy | Ferlini et al. (1994) |
| Gly47Val | GGG GTG | PN, AN, Heart | Sri Lanka | Booth et al. (1993) |
| Gly47Glu | GGG GAG | PN | Germany | Altland et al. (1999) |
| Thr49Ala | ACC GCC | Heart, PN | Italy | Almeida et al. (1992) |
| Thr49Ile | ACC ATC | PN, Heart | Japan | Nakamura et al. (1999) |
| Thr49Pro | ACC CCC | Heart | USA | Lim et al. (2002) |
| Ser50Arg | AGT AGG | PN, AN | Japan | Ueno et al. (1990)/Palha et al. 2001 |
| Ser50Ile | AGT ATT | Heart, PN, AN | Japan | Saeki et al. (1992) |
| Glu51Gly | GAG GGG | Heart | USA | Jacobson et al. (1999) |
| Ser52Pro | TCT CCT | PN, AN, Heart | UK | Booth et al. (1993)/ |
| Palha et al. (2001) | ||||
| Gly53Glu | GGA GAA | LM, Heart | France | Ellie et al. (2001) |
| Gly53Ala | GGA GCA | LM,PN | UK | Douglass et al.(2007) |
| Glu54Gly | GAG GGG | PN, AN | UK | Reilly et al. (1995) |
| Glu54Lys | GAG GAA | PN, AN, Heart | Japan | Togashi et al. (1999) |
| Glu54Leu | GAG CTG | UK | ||
| Leu55Arg | CTG CGG | LM, PN | Germany | Altland et al. (1999) |
| Leu55Pro | CTG CCG | PN, Heart, AN | Taiwan | Jacobson et al. (1992a) |
| Leu55Gln | CTG CAG | AN, PNUSA | Yazaki et al. (2002b) | |
| Leu55Glu | CTG CAG | Heart, PN, AN | Sweden | |
| His56Arg | CAT CGT | Heart | USA | Jacobson et al. (1999) |
| Gly57Arg | GGG AGG | Heart | Heart | |
| Leu58His | CTC CAC | CTS, Heart | Germany | Nichols et al. (1989) |
| Leu58Arg | CTC CGC | CTS, AN, Eye | Japan | Saeki et al. (1991) |
| Thr59Lys | ACA AAA | Heart, PN | Italy | Booth et al. (1995) |
| Thr60Ala | ACT GCT | Heart, CTS | Ireland | Wallace et al. (1986) |
| Glu61Lys | GAG AAG | PN | Japan | Shiomi et al. (1993) |
| Glu61Gly | GAG GGG | Heart,CTS | USA | Rosenzweig et al (2007) |
| Phe64Leu | TTT CTT | PN, CTS, Heart | Italy | Ii et al. (1991) |
| Phe64Ser | TTT TCT | LM, PN, Eye | Italy | Uemichi et al. (1999) |
| Gly67Glu | ||||
| Ile68Leu | ATA TTA | Heart | Germany | Almeida et al. (1991) |
| Tyr69His | TAC CAC | Eye | Scotland | Zeldenrust et al (1994) |
| Tyr69Ile | TAC ATC | CTS, Heart | Japan | Takei et al (2003) |
| Lys70Asn | AAA AAC | CTS, PN, Eye | Germany | Izumoto et al. (1992) |
| Val71Ala | GTG GCG | PN, Eye | Spain | Almeida et al. (1993) |
| Ile73Val | ATA GTA | PN, AN | Bangladesh | Booth et al. (1998) |
| Ser77Phe | TCT TTT | PN | France | Planté et al. (1998) |
| Ser77Tyr | TCT TAT | PN | Germany | Wallace et al. (1988) |
| Tyr78Phe | TAC TTC | Heart, PN | Italy | Anesi et al. (2001) |
| Ala81Val | GCA GTA | Heart | UK | |
| Ala81Thr | GCA ACA | Heart | USA | |
| Ile84Ser | ATC AGC | Heart, CTS, Eye | Switzerland | Dwulet et al. (1986) |
| Ile84Asn | ATC AAC | Eye, Heart | Italy | Skinner et al. (1992) |
| Ile84Thr | ATC ACC | Heart, PN, AN | Germany | Stangou et al. (1998) |
| His88Arg | CAT CGT | Heart | Sweden | Holmgren et al. (2005) |
| Glu89Gln | GAG CAG | PN, Heart | Italy | Almeida et al. (1992) |
| Glu89Lys | GAG AAG | PN, Heart | USA | Nakamura et al. (2000) |
| His90Asp | CAT GAT | Heart | UK | |
| Ala91Ser | GCA TCA | PN, CTS, Heart | France | Misrahi et al. (1998) |
| Gln92Lys | GAG GCT | Heart | Japan | Saito et al. (2001) |
| Val94Ala | GTA GTC | PN, Heart | USA | Bergen et al. (2004) |
| Ala97Gly | GCC GGC | Heart, PN | Japan | Yasuda et al. (1994) |
| Ala97Ser | GCC TCC | PN, Heart | France | Lachmann et al. (2000) |
| Ile107Val | ATT GTT | Heart, CTS, PN | Germany | Jacobson et al. (1994) |
| Ile107Met | ATT ATG | PN, Heart | Germany | Altand et al. (1999) |
| Ile107Phe | ATT TTT | PN, AN | UK | |
| Ala109Ser | GCC TCC | PN | Japan | Date et al. (1997) |
| Leu111Met | CTG ATG | Heart | Denmark | Nordlie et al. (1988) |
| Ser112Ile | AGC ATC | PN, Heart | Italy | De Lucia et al. (1993) |
| Tyr114Cys | TAC TGC | PN, AN, Eye | Japan | Ueno et al. (1990a) |
| Tyr114His | TAC CAC | CTS | Japan | Murakami et al. (1994) |
| Tyr116Ser | TAT TCT | PN, CTS | France | Misrahi et al. (1998) |
| Ala120Ser | GCT TCT | Heart, PN, AN | Africa | Gillmore et al. (1999) |
| Val122Ile | GTC ATC | Heart | Africa | Saraiva et al. (1990) |
| DelVal122 | GTC loss | Heart, PN, CTS | Equador/Spain | Uemichi et al. (1995) |
| Munar et al. (2000) | ||||
| Val122Ala | GTC GCC | Heart, Eye, PN | UK | Theberge et al. (1999) |
| Asn124Ser | AAT AGT | Kidney | Italy | Bergstrom et al.(2007) |
AN - autonomic neuropathy; CTS - carpal tunnel syndrome; Eye - vitreous deposition
PN - peripheral neuropathy; LM - leptomeningeal amyloid; Heart - cardiomyopathy
Non-amyloidogenic TTR mutations
Several TTR mutations without pathogenic consequences have been described and are presented in Table 2.
Table 2 - Non-amyloid TTR mutations and compound heterozygotes
Mutation | Codon change | Frequency* | Reference |
|
|
|
|
Gly6Ser | GGT AGT | 33/558 | Jacobson et al. (1995) |
Met13Ile | ATG ATC | nd | Altland et al. (1999) |
Asp74His | GAC CAC | nd | Uemichi et al. (1994) |
His90Asn | CAT AAT | 16/12,400 | Saraiva et al. (1991) |
Gly101Ser | GGC AGC | nd | Kishikawa et al. (1998) |
Pro102Arg | CCC CGC | 1/8,000 | Almeida et al. (1991a) |
Arg104Cys | CGC TGC | nd | Saraiva et al. (1999) |
Arg104His | CGC CAC | nd | Terazaki et al (1999) |
Ala108Ala** | GCC GCT | nd | Palha et al. (1997) |
Ala109Thr | GCC ACC | 1/10,000 | Alves et al. (1997) |
Ala109Val | GCC GTC | nd | Izumoto et al. (1993) |
Thr119Met | ACG ATG | 35/10,000 | Alves et al. (1997) |
Pro125Ser | CCC TCC | nd | Ferlini et al (1996) |
Compound | heterozygotes | ||
Gly6Ser/Val30Met | 7/160 | Alves et al. (1996) | |
Gly6Ser Phe33Ile*** | nd | Jacobson et al. (1994a) | |
Gly6Ser/Ala45Asp | nd | Jacobson et al. (1993) | |
Gly6Ser/Ser77Tyr | nd | Planté et al. (1999) | |
Gly6Ser/Tyr114Cys | nd | Connors et al. (1999a) | |
Gly6Ser/Thr119Met | nd | Saraiva (pers.comm) | |
Gly6Ser/Val122/Ala | nd | Theberge et al. (1999) | |
His90Asn/Val30Met | nd | Saraiva et al. (1991) | |
His90Asn Glu42Gly*** | nd | Skare et al. (1994) | |
His90Asn/Thr119Met | nd | Alves et al (1993) | |
Arg104His/Val30Met | nd | Terazaki et al (1999) | |
Thr119Met/Val30Met | nd | Alves et al (1996a) |
* Refers to mutant allele frequency** Silent mutation*** Mutations on the same allele
The allele frequency has been estimated in screening studies in different populations; this is the case of Gly6Ser present in about 12 % of the Caucasian population and the Thr119Met mutation found in about 0.8% of Portuguese and German populations investigated. Of particular importance is compound heterozygosity of non-amyloid and amyloid mutations usually occurring in different alleles. Thus, the polymorphic Gly6Ser mutation has been described in association with different amyloid mutants as documented in Table 2; this mutant does not influence the clinical outcome of Met30 carriers (Alves et al., 1996, whereas the Thr119Met and the Arg104His mutants do. Differences in clinical presentation and severity of symptoms among Portuguese and Japanese Met 30 patients carrying respectively the Met 119 and the His104 mutations are observed with a clear protective effect exerted by the non pathogenic mutant (Coelho et al. 1996; Terazaki e al. 1999), which confer more stability to the molecule. Substitutions in position 109 have been found in individuals with euthyroid hyperthyroxinemia and lead to an increase in the affinity for thyroxine. Most of non amyloidogenic as well more frequent amyloidogenic mutations such as the Val30Met mutation occur in CpG dinucleotide hotspots (Yoshioka et al. 1989).
TTR Aggregation
Each TTR monomer contains twoß-sheets, composed of strands DAGH and CBEF, which interact face-to-face through hydrogen bonds between strands HH´ and FF´ to form a dimer. In the tetramer (represented in the figure), hydrogen bonds between main chain atoms belonging to loop AB of one monomer and strand H´ from the other monomer as well as hydrophobic contacts are important.
The effects introduced by amyloidogenic mutations have been the subject of intensive study mainly by X-ray crystallography, but with the exception of the Leu55Pro mutation did not reveal drastic changes; so far, the solved structures point to a clear destabilization of the tetrameric structure of the protein. The structural studies by X-ray diffraction on the particularly aggressive mutant TTR - Leu55Pro revealed aggregation of TTR having as building blocks monomers (Sebastião et al. 1998), consistent with data from synchrotron analyses of "ex vivo" fibrils (Inoue et al. 1998) and indicated important changes in secondary structure by the disruption of strand D which becomes part of a long loop that connects strands C and E. Disruption of the D strand affects the hydrogen bonding with the A strand, exposing new surfaces involved in aggregation; in particular, the contacts of the a -helix and the AB loop are different, suggesting these regions are important in amyloidogenesis. In fact, deletion or multiple substitutions in the D strand lead to highly amyloidogenic mutants (Goldstein et al. 1999) ; destabilization of contacts between the a -helix and the AB loop such as occurs in the Tyr78Phe mutant result in a structure that is recognized by monoclonal antibodies specific for the amyloid fold (Redondo et al. 2000). When hydrophobic interactions are changed at dimer-dimer interfaces less stable tetramers with higher propensity for amyloid formation are generated (Redondo et al. 2000a). Thus, mutations in TTR that loose the AB loops of the tetramer and other dimer-dimer interactions increase the susceptibility of amyloid formation.
Physical-chemical studies of TTR from Val30Met/Thr119Met and Val30Met/Arg104His compound heterozygotic patients indicate that the protective mutant increases the resistance to dissociation of the mixed tetramer (Almeida et al. 2000). The reasons why TTR deposits as amyloid and leads to clinically heterogeneous syndromes is unknown. It might be related to the amyloidogenic potential of the protein itself, since 50% of TTR has a beta-sheet structure; that might be the reason why non-mutated TTR deposit in the heart of aged individuals in a condition termed senile systemic amyloidosis (Westermark et al. 1990).
References
Almeida, MR, Hesse A, Steinmetz A, Maisch B, Altland K, Linke RP, Gawinowicz MA, Saraiva MJ. 1991. Transthyretin Leu 68 in a form of cardiac amyloidosis. Basic Res Card 86: 567-571.
Almeida MR, Altland K, Rauh S, Gawinowicz MA, Moreira P, Costa PP, Saraiva, MJ. 1991a. Characterization of a basic transthyretin variant TTR-Arg 102 in the German population. Bioch Biophys Acta 1097: 224-226.
Almeida MR , Ferlini A, Forabosco A, Gawinowicz MA , Costa P P , Salvi F, Plasmati R, Tassinari C, Altland K, Saraiva MJ. 1992. Transthyretin variants (TTR Ala 49 and TTR Gln 89) in two Sicilian kindreds with hereditary amyloidosis. Human Mutat 1: 211-215.
Almeida MR, Andreu FL, Qués MM, Costa PP, Saraiva MJ. 1993. Transthyretin Ala 71: a new transthyretin variant in a Spanish family with familial amyloidotic polyneuropathy. Human Mutat 2: 420-421.
Almeida MR, Alves IL, Terazaki H, Saraiva MJ. 2000. Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy - TTR 104H and TTR T119M. Biochem Biophys Res Communc 270:1024-1028.
Altland K. 1999. Common molecular characteristics of amyloidogenic TTR mutations. The 4th International Symposium on FAP and other TTR related disorders. Umea, Sweden.
Alves IL, Divino C, Schussler G, Altland K, Almeida MR, Palha JA, Coelho T, Costa PP, Saraiva MJM. l993. Thyroxine binding in a TTR Met 119 kindred. J End Clin Lab 76: 484-488.
Alves IL, Jacobson DR, Torres MF, Holmgren G, Buxbaum J, Saraiva MJ. 1996. Transthyretin Ser6 as a neutral polymorphism in familial amyloidotic polyneuropathy. Amyloid 3: 242-244.
Alves IL, Jacobson DR, Torres MF, Coelho T, Holmgren G, Saraiva MJ. 1996a. Compound heterozygosity in patients with TTR-related amyloidosis. Neuromuscular Disorders (Suppl) 6: S19.
Alves IL, Altland K, Almeida MR, Winter P, Saraiva MJM 1997. Screening and biochemical characterization of transthyretin variants in the Portuguese population . Human Mutation 9: 226-233.
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. 1984. Type I familial amyloidotic polyneuropathy (Japanese type). Brain and Develop 6: 128-133.
Blake CCF, Geisow MJ, Swan IDA, Rerat C, Rerat B. 1974. Structure of human plasma prealbumin at 2.5 A resolution. A preliminary report on the polypeptide chain conformation quaternary structure and thyroxine binding. J Mol Biol 88:1-12.
Booth DR, Soutar AK, Hawkins PN, Pepys MB. 1993. Three new amyloidogenic transthyretin gene mutations advantages of direct sequencing. "In: Kisilevsky R, Benson MD, Frangione B, Gauldie J, Muckle T, Young I, editors. Amyloid and Amyloidosis. Parthenon Publishing. p 456-458.
Booth DR, Tan SY, Hawkins PN, Pepys MB, Frustaci A. 1995. A novel variant of transthyretin, 59 (Thr) - (Lys), associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation 91: 962-967.
Booth DR, Booth SE, Persey MR, Tan SY, Madhoo S, Pepys MB, Hawkins PN. 1996. Three new amyloidogenic TTR mutations: Pro 12, Glu 18, Val 33. Neuromuscular Disorders (Suppl) 6: S20.
Booth DR, Gillmore JD, Persey MR, Booth SE, Cafferty KD, Tennent GA, Madhoo S, Whitehead TC, PasvolG, Hawkins PN. 1998. Transthyretin Ile73Val is associated with familial amyloidotic polyneuropathy. Hum Mutat 12:135.
Brett M, Persey MR, Reilly MM, Revesz T, Booth DR, Booth SE, Hawkins PN, Pepys MB, Morgan-Hughes JA. 1999. Transthyretin Leu12Pro is associated with systemic neuropathic and leptomeningeal amyloidosis. Brain 122:183-190.
Carvalho M, Moreira P, Evangelista T, Ducla-Soares JL, Bento M, Fernandes R, Saraiva MJ. 2000. New transthyretin mutation V28M in a Portuguese kindred with amyloid polyneuropathy. Muscle and Nerve 23:1016-1021.
Coelho T, Chorão R, Sousa A, Alves IL, Torres MF, Saraiva MJM. 1996. Compound heterozygotes of transthyretin Met 30 and transthyretin Met 119 are protected from the devastating effects of familial amyloid polyneuropathy. Neuromuscular Disorders (Suppl) 6: S20.
Connors LH, Theberge R, Skare J, Costello CE, Falk RH, Skinner M. 1999. A new transthyretin variant (Asn23) associated with familial amyloidosis in a Portuguese patient. Amyloid 6:114-118.
Connors LH, Ericsson T, Skare J, Amico A, Jones LA, Lewis WD, Skinner M. 1999a. Screening for plasma transthyretins using isoelectric focusing (IEF), a test for familial transthyretin amyloidosis (ATTR). In: Kyle RA and Gertz MA, editors. Amyloid and Amyloidosis. Parthenon Publishing. p 303- 305.
Date Y, Nakazato M, Kangawa K, Shirieda K, Fujimoto T, and Matsukura S. 1997. Detection of three transthyretin gene mutation in familial amyloidotic polyneuropathy by analysis of DNA extracted form formalin-fixed and paraffin-embedded tissues. J Neurol Sci. 150:143-148.
De Lucia R, Mauro A, Di Scapio A, Buffo A, Mortara P, Orsi L, Schiffer D. 1993. A new mutation on the transthyretin gene (Ser 112 Ile) causes an amyloid neuropathy with severe cardiac impairment. Clin Neuropathol 12:S44.
Dupuy O, Bletry O, Blanc AS, Droz D, Viemont M, Delpech M, Grateau G. 1998. A novel variant of transthyretin (Glu42Asp) associated with sporadic late-onset cardiac amyloidosis. Amyloid 5:285-287.
Dwulet FE, Benson MD. 1986. Characterization of a transthyretin (prealbumin) variant associated with familial amyloidotic polyneuropathy type II (Indiana/Swiss). J Clin Invest 78: 880-886.
Ferlini A, Salvi F, Patrosso C, Fini S, Vezzoni P, Forabosco A. 1994. A new mutation (TTR Ala-47) in the transthyretin gene associated with hereditary amyloidosis TTR-related. Hum Mutation 4: 61-64.
Ferlini A, Rapezzi C, Magnani B, Winter P, Altland K, Vezzoni P, Patrosso MC. 1996. A compound heterozygous patient for two TTR mutations affected with restrictive amyloidotic cardiomyopathy. Neuromuscular Disorders (Suppl) 6: S23.
Gillmore JD, Booth DR, Pepys MB, and Hawkins PN. 1999. Familial amyloid polyneuropathy in an Afro-Caribbean patient associated with a novel transthyretin variant, serine 120. The 4th International Symposium on FAP and other TTR related disorders. Umea, Sweden.
Goldsteins G, Persson H, Andersson K, Olofsson A, Dacklin I, Edvinsson, Saraiva MJ, Lundgren E. 1999. Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants. Proc Natl Acad Sci U S A 96:3108-3113.
Holmgren G, Haetner E, Nordenson I, Sandgren O, Steen L, Lundgren E. 1988. Homozygosity for the transthyretin- met 30- gene in two Swedish sibs with familial amyloidotic polyneuropathy. Clin Gen 34: 333-338.
Holmgren G, Costa PMP, Andersson C, Asplund K, Steen L, Beckman L, Nylander PO, Teixeira A, Saraiva MJM, Costa PP. 1994. Geographical distribution of TTR met30 carriers in northern Sweden: discrepancy between carrier frequency and prevalence rate. J Med Genetics 31:351-354.
Ii S, Minnerath S, Ii K, Dyck PJ, Sommer SS. l991. Two tiered DNA based diagnosis of transthyretin amyloidosis reveals two novel point mutations. Neurology 41: 893-898.
Inoue H, Domingues FS, Damas AM, Saraiva MJ, Lundgren E, Sandgren O, Kirschner DA. 1998. Analysis of x-ray diffraction patterns from amyloid of biopsied vitreous humor and kidney of transthyretin (TTR) Met30 familial amyloidotic polyneuropathy (FAP) patients: axially arrayed TTR monomers constitute the protofilament. Amyloid 5:163-74.
Izumoto S, Martone RL, Younger D, Hays AP, Herbert J. 1992. Familial amyloidotic polyneuropathy presenting with carpal tunnel syndrome and a new transthyretin mutation: Asn 70. Neurology 42: 2094-2102.
Izumoto S, Kornberg J, Herbert J. 1993. Two transthyretin mutations associated with euthyroid hyperthyroxinemia. J Reumatol 20:186.
Jacobson DR, McFarlin DE, Kane I, Buxbaum JN. 1992. Transthyretin Pro55, a variant associated with early-onset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement. Hum Genet 89:353-356.
Jacobson D, Gertz MA, Kane I, Buxbaum JN. 1993. Genetic analysis of 9 unrelated patients with transthyretin (TTR)-cardiac amyloidosis: correlation of clinical and genetic findings and description of 2 new TTR variants. In: Kisilevsky R, Benson MD, Frangione B, Gauldie J, Muckle T, Young I, editors. Amyloid and Amyloidosis. Parthenon Publishing. p 474-476.
Jacobson D, Gertz MA, Buxbaum JN. 1994). Transthyretin Val 107, a new variant associated with familial cardiac and neuropathic amyloidosis. Human Mutation 3: 399-401.
Jacobson DR, Buxbaum JN. 1994a. A double-variant transthyretin allele (Ser 6, Ile 33) in the Israeli patient "SKO" with familial amyloidotic polyneuropathy. Human Mutation 3: 254-260.
Jacobson DR, Alves IL, Saraiva MJ, Thibodeau SN, Buxbaum JN. 1995. Transthyretin Ser6 gene frequency in individuals without amyloidosis. Hum Genet 95:308-312.
Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum J. 1997. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. The New England Journal of Medicine 336: 466-473.
Jacobson DR, Kane I, Pan T, Tufau P, Gertz MA, Gallo G, Buxbaum JN. 1999. Late-onset cardiac amyloidosis and transthyretin variants: distinguishing between senile cardiac amyloidosis and familial amyloid cardiomyopathy. The 4th International Symposium on FAP and other TTR related disorders. Umea, Sweden.
Janunger T, Anan I, Holmgren G, Lovheim O, Ohlsson PL, Suhr OB, Tashima K. 2000. Heart failure caused by a novel amyloidogenic mutation of the transthyretin gene. Amyloid 7:137-140.
Jenne DE, Denzel K, Blatzinger P, Winter P, Obermaier B, Linke RP, Altland K. 1996. A new isoleucine substitution Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis. Proc Natl Acad Sci USA 93: 6302-6307.
Jones LA, Skare J, Harding J, Cohen A, Milunsky A, Skinner M .l991. Proline at position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy. Am J Human Genetics 48:979-982.
Jones LA, Skare JC, Cohen AS, Harding JA, Milunsky A, Skinner M. l992. Familial amyloid polyneuropathy: a new transthyretin position 30 mutation (alanine for valine) in a family of German descent. Clin Genet 41: 70-73.
Kishikawa M, Nakanishi T, Miyazaki A, Hatanaka M, Shimizu A, Tamoto S, Ohsawa N, Hayashi H, and Kanai M. 1998. A new non-amyloid transthyretin variant, [G101S], detected by electrospray ionization / mass spectrometry. Hum Mutat 12:363.
Kishikawa M, Nakanishi T, Miyazaki A, Shimizu A, Kusaka H, Fukui M, Nishine T. 1999. A new amyloidogenic transthyretin variant [D38A] detected by electrospray ionization/mass spectrometry. Amyloid 6:278-281.
Klein CJ, Nakamura M, Jacobson DR, Lacy MQ, Benson MD, Petersen RC. 1998. Transthyretin amyloidosis (serine 44) with headache, hearing loss, and peripheral neuropathy. Neurology 51:1462-1464.
Lachmann HJ, Booth DR, Bybee A, Hawkins PN. 2000. Transthyretin Ala97Ser is associated with familial amyloidotic polyneuropathy in a chinese-taiwanese family. Hum Mutat 16:180.
Misrahi M, Planté-Bordeneuve V, Lalu T , Serre L, Adams D, Lacroix DC, Said G. 1998. New transthyretin variants Ser91 and Ser116 associated with familial amyloidotic polyneuropathy. Hum Mutat 12: 71.
Munar-Qués M, Costa PP, Saraiva MJM, Farré CV, Bernat CM, Luna CC, Alberti JFF. 1997. Familial amyloidotic polyneuropathy. TTR Met 30 in Majorca (Spain). Amyloid 4: 181-186.
Munar-Qués M, Saraiva MJ, Calonge JO, Moreira P, Vidal PR, Pujol XP, Abel MJ, Alter JMB. 2000. Familial amyloid polyneuropathy in a Spanish family with a transthyretin deletion (Val122) presenting with carpal tunnel syndrome. Clin Genet 58: 411-412.
Murakami T, Maeda S, Yi S, Ikegawa S, Kawashima E, Onodera S, Shimada K, Araki S. 1992. A novel transthyretin mutation associated with familial amyloidotic polyneuropathy. Biochem Biophys Res Communic 182: 520-526.
Murakami T, Tachibana S, Endo Y, Kawai R, Hara M, Tanase S, Ando M. 1994. Familial carpal tunnel syndrome due to amyloidogenic transthyretin His 114 variant. Neurology 44: 315-318.
Nakamura M, Yamashita T, Ando Y, Hamidi Asi K, Tashima K, Ohlsson P, Kukuse Y, Benson MD. 1999. Identification of a new transthyretin variant (Ile49) in familial amyloidotic polyneuropathy using electrospray ionization mass spectrometry and nonisotopic Rnase cleavage assay. Hum Hered 49: 186-189.
Nakamura M, Asl KH, Benson MD. 2000. A novel variant of transthyretin (Glu89Lys) associated with familial amyloidotic polyneuropathy. Amyloid 7:46-50.
Nakazato M, Kangawa K, Minamino N, Tawara S, Matsuo H, Araki S. 1984. Revised analysis of amino acid replacement in a prealbumin variant (SKO-III) associated with familial amyloidotic polyneuropathy of Jewish origin. Biochem Biophys Res Commun 123: 921-928.
Nakazato M, Ikeda S, Shiomi K, Matsukura S, Yoshida K, Shimizu H, Atsumi T, Kangawa K, Matsuo H. 1992. Identification of a novel transthyretin variant (Val30 Leu) associated with familial amyloidotic polyneuropathy. FEBS Letters 306:206-208.
Nichols WC, Liepnieks JJ, McKusick VA, Benson MD. 1989. Direct sequencing of the gene for Maryland/German familial amyloidotic polyneuropathy type II and genotyping by allele-specific enzymatic amplification. Genomics 5, 535-540.
Nishi H, Kimura A, Harada H, Hayashi Y, Nakamura M, Sasazuki T. 1992. Novel variant transthyretin gene (Ser 50 to Ile) in familial cardiac amyloidosis. Biochem Biophys Res Commun 187: 460-466.
Nordlie M, Sletten K, Husby G, Ranlov PJ. 1988. A new prealbumin variant in familial amyloidotic cardiomyopathy of Danish origin. Scand J Immunol 27: 119-122.
Palha JA, Moreira P, Wisniewski T, Frangione B, Saraiva MJ. 1997. C for T substitution at codon 108: the first identified silent mutations in the transthyretin gene. Amyloid 4: 52-53.
Patrosso MC, Salvi F, DeGrandis D, Vexoni P, Jacobson DR, Ferlini A. 1998. Novel transthyretin missense mutation (Thr34) in an Italian family with hereditary amyloidosis. Am J Med Genet 77:135-138.
Petersen RB, Goren H, Cohen M, Richardson SL, Tresser N, Lynn A, Gali M, Estes M, Gambetti P. 1997. Transthyretin amyloidosis: a new mutation associated with dementia. Ann Neurol 41:70-73.
Plante-Bordeneuve V, Lalu T, Misrahi M, Reilly MM, Adams D, Lacroix C, Said G. 1998. Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. Neurology 51:708-714.
Planté-Bordeneuve V, Ferreira A, Misrahi M, Adams D, Said G. 1999. Genotypic and phenotypic spectrum of transthyretin amyloidosis in the French population. The 4th International Symposium on FAP and other TTR related disorders. Umea, Sweden.
Redondo C, Damas AM, Olofsson A, Lundgren E, Saraiva MJ. 2000. Search for intermediate structures in transthyretin fibrillogenesis: soluble tetrameric Tyr78Phe TTR expresses a specific epitope present only in amyloid fibrils. J Mol Biol 304: 461-470.
Redondo C, Damas AM, Saraiva MJ. 2000a. Designing transthyretin mutants affecting tetrameric structure: implications in amyloidogenicity. Biochem J. 348:167-172.
Reilly MM, Adams D, Booth DR, Davis MB, Said G. 1995. Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy. Brain 118:849-856.
Saeki Y, Ueno S, Yorifuji S, Sugiyama Y, Ide Y, Matsuzawa Y. l991. New mutant gene (transthyretin Arg 58) in cases with hereditary polyneuropathy detected by non-isotope method of single-strand conformation polymorphism analysis. Biochem Biophys Res Commun 180: 380-385.
Saeki Y, Ueno S, Takahashi N, Soga F, Yanagihara T. 1992. A novel mutant (Transthyretin Ile 50) related to amyloid polyneuropathy- single-strand conformation polymorphism as a new genetic marker. FEBS Letters 308: 35-37.
Saraiva MJM, Birken S, Costa PP, Goodman DS. 1984. Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin). J Clin Invest 74:104-119.
Saraiva, MJM, Sherman W, Marboe C, Figueira A, Costa PP, Freitas AF, Gawinowicz MA. l990. Cardiac amyloidosis: report of a patient heterozygous for the transthyretin isoleucine 122 variant. Scand J Immunol 32: 341-346.
Saraiva, MJM, Almeida MR, Alves IL, Moreira P, Gawinowicz MA, Costa PP, Rauh S, Banhzoff A, Altland K. l991. Molecular analyses of an acidic transthyretin Asn 90 variant. Am J Hum Genet 48:1004-1008.
Saraiva MJ, Almeida MR, Sherman W, Gawinowicz MA, Costa PM, Costa PP, Goodman DS. 1992. A new transthyretin mutation associated with amyloid cardiomyopathy. Am J Hum Genet 50:1027-1030.
Saraiva, MJM, Torres MF, Serra J, Ochoa J. 1999. A new transthyretin variant - ATTR Arg104Cys. Amyloid 6:149-151.
Sasaki H, Sakaki Y, Matsuo H, Goto I, Kuroiwa Y, Sahashi I, Takahashi A, Shinoda T, Isobe T, Takagi Y. 1984. Diagnosis of familial amyloidotic polyneuropathy by recombinant DNA techniques. Biochem Biophys Res Commun 125: 636-642.
Sebastiao MP, Saraiva MJ, Damas, AM. 1998. The crystal structure of amyloidogenic Leu55 --> Pro transthyretin variant reveals a possible pathway for transthyretin polymerization into amyloid fibrils. J Biol Chem. 273:24715-24722.
Shiomi K, Nakazato M, Matsukura S, Ohnishi A, Hatanaka H, Tsuji S, Murai Y, Kojima M, Kangawa K, Matsuo H. 1993. A basic transthyretin variant (Glu61 Lys) causes familial amyloidotic polyneuropathy: protein and DNA sequencing and PCR-induced mutation restriction analysis. Biochem Biophys Res Communic 194: 1090-1096.
Skare J, Jones LA, Myles N, Kane K, Milunsky A, Cohen A, and Skinner M. 1994. Two transthyretin mutations (glu42gly, his90asn) in an Italian family with amyloidosis. Clin Genet 45:281-284.
Skinner M, Harding J, Skare I, Jones LA, Cohen AS, Milunsky A, Skare J. l992. A new transthyretin mutation associated with amyloidotic vitreous opacities- Asparagine for isoleucine at position 84. Ophtalmology 99: 503-508.
Sousa A, Coelho T, Barros J, Sequeiros J. 1995. Genetic epidemiology of familial amyloidotic polyneuropathy (FAP)-Type I in Póvoa do Varzim and Vila do Conde (North of Portugal). Am J Med Genetics 60: 512-521.
Stangou AJ, Hawkins PN, Heaton ND, Rela M, Monaghan M, Nihoyannopoulos P, O’Grady J, Pepys MB, Williams R. 1998. Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy: implications for amyloid fibrillogenesis. Transplantation 66:229-233.
Terazaki H, Ando Y, Misumi S, Nakamura M, Ando E, Matsunaga N, Shoji S, Okuyama M, Ideta H, Nakagawa K, Ishizaki T, Ando M, Saraiva MJ. 1999. A novel compound heterozygote (FAP ATTR Arg104His/Val30Met) with high serum transthyretin (TTR) and retinol binding protein (RBP) levels. Biochem Biophys Res Commun 264: 365-370.
Theberge R, Connors L, Skare J, Skinner M, Falk RH, Costello CE. 1999. A new amyloidogenic transthyretin variant (Val122Ala) found in a compound heterozygous patient. Amyloid 6:54-58.
Togashi S, Watanabe H, Nagasaka T, Shindo K, Shiozawa Z, Maeda S, Tawata M, Onaya T. 1999. An aggressive familial amyloidotic polyneuropathy caused by a new variant transthyretin Lys 54. Neurology 53:637-639.
Uemichi T, Murrell JR, Zeldenrust S, Benson MD. 1992. A new mutant transthyretin (Arg 10) associated with familial amyloid polyneuropathy. J Med Genet 29:888-891.
Uemichi T, Liepniecks JJ, Altland K, Benson MD. 1994. Identification of a novel non-amyloidogenic transthyretin polymorphism (His-74) in the German population. Amyloid 1: 149-153.
Uemichi T, Gertz MA, Benson MD. 1995. A new transthyretin variant (Ser24) associated with familial amyloid polyneuropathy. J Med Genet 32:279-281
Uemichi T, Liepniecks JJ, Benson MD. 1997. A trinucleotide deletion in the transthyretin gene (delta V122) in a kindred with familial amyloidotic polyneuropathy. Neurology 48:1667-1670.
Uemichi T, Uitti RJ, Koeppen AH, Donat JR, Benson MD. 1999. Oculoleptomeningeal amyloidosis associated with a new transthyretin variant Ser64. Arch Neurol 56:1152-1155.
Ueno S, Uemichi T, Takahashi N, Soga F, Yorifuji S, Tarui S. 1990. Two novel variants of TTR identified in Japanese cases with familial amyloidotic polyneuropathy. Biochem Biophys Res Commun 169: 1117-1121.
Ueno S, Uemichi T, Yorifuji S, Tarui S. 1990a. A novel variant of transthyretin (Tyr 114 to Cys) deduced from the nucleotide sequences of the gene fragments from familial amyloidotic polyneuropathy in Japanese sibling cases. Biochem Biophys Res Commun 169: 143-147.
Vidal R, Garzuly F, Budka H, Lalowski M, Linke RP, Brittig F, Frangione B,
last updated: February 2001