Transthyretin amyloidosis

Familial transthyretin amyloidosis (ATTR) is a hereditary degenerative disease which is closely associated with single amino acid substitutions in the plasma protein transthyretin (TTR), a 127 amino acid protein (Mr 13,761 Da) that is tetrameric in its native state.28 The clinical manifestations of ATTR are related to specific mutations of TTR (e.g., Val30 - Met and Thr60 — Ala). The definitive diagnosis is often established on the basis of the... 

Connors, L. H., Ericsson, T., Skare, J., Jones, L. A., Lewis, W. D., and Skinner, M. (1998). A simple screening test for variant transthyretins associated with Familial transthyretin amyloidosis using isoelectric focusing. Biochim. Biophys. Acta 1407, 185-192. 

Holmgren, G., Ericzon, B.G., Groth, C.G., Stein, L., Suhr, O., Andersen, O., Wallin, B.G., Seymour, A., Richardson, S., Hawkins, P.N., Petys, MJ. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993 341 1113-1116... 

Excellent results have been reported with RNAi therapy in transthyretin amyloidosis [620]. Transthyretin amyloidosis is produced by deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the cardiovascular system. Coelho et al. 

Transthyretin amyloidosis (also called familial amyloid polyneuropathy) is an autosomal dominant syndrome characterized by peripheral neuropathy. This disease results from one of five mutations identified thus far in the gene for transthyretin. Transthyretin is also called prealbumin (although it has no structural relationship to albumin) because it migrates ahead of albumin in standard electrophoresis at pH 8.6. Transthyretin is synthesized in the liver and is a normal plasma protein with a concentration of 20-40 mg/dL. It transports thyroxine and retinol binding protein (Chapter 38). The concentration of transthyretin is significantly decreased in malnutrition and plasma levels are diagnostic of disorders of malnutrition (Chapter 17). 

Familial amyloidoses are rare autosomal dominant disorders encompassing more than seven different genes and protein products. Transthyretin amyloidosis (ATTR) is the most common hereditary form of the disease, newly affecting... 

Transthyretin Amyloidosis Inhibitors Containing Carborane Pharmacophores... 

R. L. Julius, O. K. Farha, J. Chiang, L. J. Perry, M. F. Hawthorne, Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carhorane pharmacophors, Proc. Nat. Acad. Sci. USA, 2007,104, 4808-4813. 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

Transthyretin is a 147-residue transporter protein that is deposited as amyloid in senile systemic amyloidosis and familial amyloid polyneuropathy (Benson and Uemichi, 1996 Saraiva, 1995 Westermark et al., 1990). The protein s native structure is a 55-kDa dimer of dimers, or homotetramer, composed mainly of /1-sheets (Blake et al., 1978). The native monomer-to-monomer interface is formed by mutual, antiparallel extension of each monomer s two sheets (Fig. 7A) both four-stranded sheets in the monomers (DAGH and GBEF) become eight-stranded sheets in the dimer (DAGHH G A D and CBEFF E B C ) (Blake et al, 1978). In vitro at low... 

Westermark, P., Sletten, K.,Johansson, B., and Cornwell, G. G., Ill (1990). Fibril in senile systemic amyloidosis is derived from norma] transthyretin. Proc. Natl. Acad. Sci. USA 87, 2843-2845. 

E De Lorenzi, C Galbusera, V Bellotti, P Mangione, G Massolini, E Tabolotti, A Andreola, G Caccialanza. Affinity capillary electrophoresis is a powerful tool to identify transthyretin-binding drugs for potential therapeutic use in amyloidosis. Electrophoresis 21 3280—3289, 2000. 

Familial Amyloidosis. Several genetically transmitted forms of amyloid disease have been reported. These have primarily neurological but also renal and vascular symptoms (Table 20-14), The fibrils of the Portuguese and Swedish syndromes and the polyneuropathic amyloid syndrome of Ashkenazic Jews have monomers of 14 kDa that share antigenic determinants and amino acid homology with prealbumin (transthyretin). 

The structure of transthyretin. The molecule contains eight antiparallel A-strands (A-H) arranged in two parallel planes. The circulating form of transthyretin is a tetramer. Some mutations in the transthyretin gene are associated with amyloidosis and eight of the amino acid alterations causing this disease are indicated. In plasma, transthyretin is a tetramer composed of identical monomers. It appears that mutations cause the monomeric unfolded intermediate of transthyretin to aggregate into an insoluble A-amyloid fibril formation. 

Bergstrom J, Murphy C, Eulitz M, Weiss DT, Westermark GT, Solomon A, Westermark P (2001) Codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis. Biochem Biephys Res Commun 285 903—908... 

Bergstrom J, Mur[4iy CL, Weiss DT, Solomon A, Sletten K, Heilman U, Westermark P (2004) Two different types of amyloid deposits— apolipoprotein A-IV and transthyretin— in a patient with systemic amyloidosis. Lab Invest 84 981-988... 

Senile systemic or age-related amyloidosis (SSA) results from the misfolding of wild-type transthyretin protein. Age-related amyloidosis occurs in systemic and localized (isolated atrial amyloid, senile aortic amyloidosis) forms. Elderly men are almost uniformly involved. Ng et al. (49) recently reported 18 SSA patients ranging in age from 67 to 86 years. 

Ueda M, Ando Y, Haraoka K, et al. Aging and transthyretin-related amyloidosis pathologic examinations in pulmonary amyloidosis. Amyloid 2006 13(1) 24—30. Ng B, Connors LH, Davidoff R, et al. Senile systemic amyloidosis presenting with heart failure a comparison with light chain-associated amyloidosis. Arch Intern... 

Westermark P, Bergstrom J, Solomon A, et al. Transthyretin-derived senile systemic amyloidosis clinicopathologic and structural considerations. Amyloid 2003 10 (suppl l) 48-54. 

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