Abstract
Transthyretin (TTR) Ser 6 was originally described in a Scottish kindred without amyloidosis. This variant, arising from a G→A transition in codon 6 that destroys an MspI site and creates a BsrI site, was present in none of 50 controls, and was therefore throught to be rare. This variant has subsequently been found in a normal human cDNA liver library and in two unrelated patients with familial amyloidosis and other TTR variants, raising the question whether it is actually a common polymorphism. To address this question, we performed PCR and restriction digestion of 574 DNA samples from people without evidence of amyloidosis or a known family history of amyloidosis. The TTR Ser 6 allele frequency was 33/558 (.060) in Caucasians (including 8/192 (.04)) in North American Ashkenazic Jews, 16/218 (.07) in North American non-Jews, and 9/148 (.06) in Portuguese), 3(242 (.01) in African Americans, 0/140 in Africans, and 0/208 in Asians. These data are most suggestive of a single Caucasian founder and the known 25% admixture of “Caucasian” genes in the African-American population. Alternatively, as this variant arose from a transition at a CG dinucleotide “hot spot,” it may have arisen on multiple occasions. These data indicate that TTR Ser 6 is a common non-amyloidogenic population polymorphism in Caucasians.
Similar content being viewed by others
References
Akbari MT, Fitch NJ, Farmer M, Docherty K, Sheppard MC, Ramsden DB (1990) Thyroxine-binding prealbumin gene polymorphism: a population study. Clin Endocrinol 33:155–160
Almeida MR, Alves IL, Sakaki Y, Costa PP, Saraiva MJM (1990) Prenatal diagnosis of familial amyloidotic poly neuropathy: evidence for an early expression of the associated transthyretin methionine 30. Hum Genet 85:623–626
Almeida MR, Altland K, Rauh S, Gawinowicz MA, Moreira P, Costa PP, Saraiva MJ (1991) Characterization of a basic transthyretin variant — TTR Arg 102 — in the German population. Biochim Biophys Acta 1097:224–226
Alves IL, Altland K, Almeida MR, Beecher P, Costa PP, Saraiva MJM (1993a) Screening of TTR variants in the Portuguese population by HIEF (abstract). J Rheumatol 20:185
Alves IL, Divino CM, Schussler GC, Altland K, Almeida MR, Palha JA, Coelho T, Costa PP (1993 b) Thyroxine binding in a TTR Met 119 kindred. J Clin Endocrinol Metab 77:484–488
Blake CCF, Geisow MJ, Oatley SJ (1978) Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 Å. J Mol Biol 121:339–356
Chakraborty R, Kamboh MI, Nwankwo M, Ferrell RE (1992) Caucasian genes in American blacks: new data. Am J Hum Genet 50:145–155
Cohen AS, Steen L (1993) Familial amyloidosis: hereditary systemic disease of the connective tissue and other organs. J Rheumatol 20:4–6
Cooper DN, Krawczak M (1990) The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet 85:55–74
Curtis AJ, Scrimshaw BJ, Topliss DJ, Stockigt JR, George PM, Barlow JW (1994) Thyroxine binding by human transthyretin variants: mutations at position 119, but not position 54, increase thyroxine binding affinity. J Clin Endocrinol Metab 78:459–462
Fitch NJS, Akbari MT, Ramsden DB (1991) An inherited non-amyloidogenic transthyretin variant, [Ser6]-TTR, with increased thyroxine-binding affinity, characterized by DNA sequencing. J Endocrinol 129:309–313
Gafni J, Fischel B, Reif R, Yaron M, Pras M (1985) Amyloidotic polyneuropathy in a Jewish family: evidence for the genetic heterogeneity of the lower limb familial amyloidotic neuropathies. Q J Med 55:33–43
Harrison HH, Gordon ED, Nichols HC, Benson MD (1991) Biochemial and clinical characterization of prealbuminChicago: an apparently benign variant of serum prealbumin (transthyretin) discovered with high-resolution two-dimensional electrophoresis. Am J Med Genet 39:442–452
Holmgren G, Haettner E, Nordenson I, Sandgren O, Steen L, Lundgren E (1988) Homozygosity for the transthyretin-met30gene in two Swedish sibs with familial amyloidotic polyneuropathy. Clin Genet 34:333–338
Ii S, Sobell JL, Sommer SS (1992) From molecular variant to disease: initial steps in evaluating the association of transthyretin M119with disease. Am J Hum Genet 50:29–41
Jacobson DR, Buxbaum JN (1991) Genetic aspects of amyloidosis. Adv Hum Genet 20:69–123
Jacobson DR, Buxbaum JN (1994) A double variant transthyretin allele (Ser 6, Ile 33) in the Israeli patient “SKO” with familal amyloidotic polyneuropathy. Hum Mutat 3:254–260
Jacobson DR, Gorevic PD, Buxbaum JN (1990) A homozygous transthyretin variant associated with senile systemic amyloidosis: evidence for a late-onset disease of genetic etiology. Am J Hum Genet 47:127–136
Jacobson DR, Reveille JD, Buxbaum JN (1991) Frequency and genetic background of the position 122 (Val→Ile) transthyretin gene in the black population. Am J Hum Genet 49:192–198
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
Kanda Y, Goodman DS, Danfield RE, Morgan FJ (1974) The amino acid sequence of human plasma prealbumin. J Biol Chem 249:6796–6805
Lalloz MRA, Byfield PGH, Himsworth RL (1984) A prealbumin variant with an increased affinity for T4 and reverse-T3. Clin Endocrinol 21:331–338
Lalloz MRA, Byfield PGH, Goel KM, Loudon MM, Thomson JA, Himsworth RL (1987) Hyperthyroxinemia due to the coexistence of two raised affinity thyroxine-binding proteins (albumin and prealbumin) in one family. J Clin Endocrinol Metab 64:346–352
Moses AC, Rosen HN, Moller DE, Tsuzaki S, Haddow JE, Lawlar J, Liepnieks JJ, Nichols WC, Benson MD (1990) A point mutation in transthyretin increases affinity fo thyroxine and produces euthyroid hyperthyroxinema. J Clin Invest 2025–2033
Murrell JR, Schoner RG, Liepnieks JJ, Rosen HN, Moses AC, Benson MD (1992) Production and functional analysis of normal and variant recombinant human transthyretin proteins. J Biol Chem 267:16595–16600
Nordvåg BY, Nilsen I, Husby G, El-Gewely MR (1991) Isolation and reconstruction of a gene from a human cDNA library by PCR. Methods Mol Cell Biol 2:161–168
Ott J (1985) Genetic markers. In: Analysis of human genetic linkage. Johns Hopkins University Press, Baltimore, pp 13–21
Rosen HN, Moses AC, Murrell JR, Liepnieks JJ, Benson MD (1993) Thyroxine interactions with transthyretin: a comparison of 10 different naturally occurring human transthyretin variants. J Clin Endocrinol Metab 77:370–374
Saraiva MJM, Sherman W, Marboe C, Figueira A, Costa P, De Freitas AF, Gawinowicz MA (1990) Cardiac amyloidosis: reort 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 M, Costa PP, Rauh S, Banzhoff A, Altland K (1991) Molecular analyses of an acidic transthyretin Asn 90 variant. Am J Hum Genet 48:1004–1008
Saraiva MJM, Costa PP, Goodman DS (1993) Transthyretin and familial amyloidotic polyneuropathy. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, Kunkel LM (eds) The molecular and genetic basis of neurological disease. Butterworths, London, pp 889–894
Scrimshaw BJ, Fellowes AP, Palmer BN, Croxson MS, Stockigt JR, George PM (1992) A novel variant of transthyretin (prealbumin), Thr119 to Met, associated with increased thyroxine binding. Thyroid 2:21–26
Strahler JR, Rosenblum BB, Hanash SM (1987) Identification and characterization of a human transthyretin variant. Biochem Biophys Res Commun 148:471–477
Yoshioka K, Furuya H, Sasaki H, Saraiva MJM, Costa PP, Sakaki Y (1989) Haplotype analysis of familial amyloidotic polyneuropathy: evidence for multiple origins of the Val-Met mutation most common to the disease. Hum Genet 82:9–13
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jacobson, D.R., Alves, I.L., Saraiva, M.J. et al. Transthyretin Ser 6 gene frequency in individuals without amyloidosis. Hum Genet 95, 308–312 (1995). https://doi.org/10.1007/BF00225199
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00225199