See also:


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

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)
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


Codon change










Jacobson et al. (1995)




Altland et al. (1999)




Uemichi et al. (1994)




Saraiva et al. (1991)




Kishikawa et al. (1998)




Almeida et al. (1991a)




Saraiva et al. (1999)




Terazaki et al (1999)




Palha et al. (1997)




Alves et al. (1997)




Izumoto et al. (1993)




Alves et al. (1997)




Ferlini et al (1996)





Alves et al. (1996)

Gly6Ser Phe33Ile***


Jacobson et al. (1994a)



Jacobson et al. (1993)



Planté et al. (1999)



Connors et al. (1999a)



Saraiva (pers.comm)



Theberge et al. (1999)



Saraiva et al. (1991)

His90Asn Glu42Gly***


Skare et al. (1994)



Alves et al (1993)



Terazaki et al (1999)



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).


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