Abstract
Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T4) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the amino-acid substitutions alone do not completely explain the variability in disease penetrance, pathology and clinical course. To analyze the factors possibly contributing to this phenotypic variability, we characterized the variations within the wild-type and mutant (Val30Met) TTR genes and their flanking sequences by performing extended microsatellite haplotype analyses, sequencing and single-nucleotide polymorphism haplotyping of genomic DNA from Portuguese and Swedish carriers of V30M. We identified 10 new polymorphisms in the TTR untranslated regions, eight resulting from single-base substitutions and two arising from insertion/deletions in dinucleotide repeat sequences. The data suggest that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456), but not by the immediately 5′- and 3′-flanking sequences of TTR. During the course of these studies, we also encountered the first instance in which the previously described intragenic haplotype III may be associated with V30M FAP in the Portuguese population.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Andrade C : A peculiar form of peripheral neuropathy. Familial atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 1952; 75: 408–427.
Sousa A, Coelho T, Lobato L, Sequeiros J : Genetic epidemiology of familial amyloidotic polyneuropathy (FAP)-type I (FAP-MET30). in Kyle R (ed): Amyloid and amyloidosis. New York and London: Parthenon; 1995, pp 209–211.
Coutinho P, Silva AM, Lima JL, Barbosa AR : Forty years of experience with type I amyloid neuropathy. Review of cases. in Glenner GG, Costa PP and Freitas AF (eds): Amyloid and amyloidosis. Amsterdam: Plenum Press; 1980, pp 88–98.
Coelho T, Sousa A, Lourenco E, Ramalheira J : A study of 159 Portuguese patients with familial amyloidotic polyneuropathy (FAP) whose parents were both unaffected. J Med Genet 1994; 31: 293–299.
Sousa A, Coelho T, Lobato L, Sequeiros J : Anticipation of age-at-onset in Portuguese patients with familial amyloid polyneuropathy-type I (FAP-MET30). in Kyle R et al (eds): Amyloid and amyloidosis. New York and London: Parthenon; 1999, pp 209–211.
Soares M, Buxbaum J, Sirugo G et al: Genetic anticipation in Portuguese kindreds with familial amyloidotic polyneuropathy is unlikely to be caused by triplet repeat expansions. Hum Genet 1999; 104: 480–485.
Andersson R : Familial amyloidosis with polyneuropathy. A clinical study based on patients living in Northern Sweden. Acta Med Scand 1976; 590: 1–64.
Sousa A, Andersson R, Drugge U, Holmgren G, Sandgren O : Familial amyloidotic polyneuropathy in Sweden: geographical distribution, age of onset, and prevalence. Hum Heredity 1993; 43: 288–294.
Tashima K, Ando Y, Tanaka Y, Uchino M, Ando M : Change in the age of onset in patients with familial amyloidotic polyneuropathy type I. Intern Med 1995; 34: 748–750.
Yoshioka K, Furuya H, Sasaki H, Saraiva MJM, Costa PP, Sakaki Y : Haplotype analysis of familial amyloidotic polyneuropathy. Evidence for multiple origins of the Val-Met mutation most common to the disease. Hum Genet 1989; 82: 9–13.
Ii S, Sommer SS : The high frequency of TTR M30 in familial amyloidotic polyneuropathy is not due to a founder effect. Hum Mol Genet 1993; 2: 1303–1305.
Waits RP, Uemichi T, Benson MD : Haplotype analysis of the transthyretin gene: evidence for multiple recurrence of the Met30 mutation in the Caucasian population. Amyloid Int J Exp Clin Investig 1995; 2: 114–118.
Baker D, Schafer M, White R : Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell 1984; 36: 131–138.
Cooper DN, Youssoufian H : The CpG dinucleotide and human genetic disease. Hum Genet 1988; 78: 151–155.
Almeida MR, Alves IL, Sakaki Y, Costa PP, Saraiva MJM : Prenatal diagnosis of familial amyloidotic polyneuropathy: evidence for an early expression of the associated transthyretin methionine 30. Hum Genet 1990; 85: 623–626.
Sakaki Y, Yoshioka K, Tanahashi H, Furuya H, Sasaki H : Human transthyretin (prealbumin) gene and molecular genetics of familial amyloidotic polyneuropathy. Mol Biol Med 1989; 6: 161–168.
Clark AG : Inference of haplotypes from PCR-amplified samples of diploid populations. Mol Biol Evol 1990; 7: 111–122.
Freeman G, Halton JH : Note on an exact treatment of contingency, goodness of fit and other problems of significance. Biometrika 1951; 38: 141–149.
Whitehead AS, Skinner M, Bruns GAP et al: Cloning of human prealbumin complementary DNA. Localization of the gene to chromosome 18 and detection of a variant prealbumin allele in a family with familial amyloid polyneuropathy. Mol Biol Med 1984; 2: 411–423.
Alves IL, Jacobson DR, Torres MF, Holmgren G, Buxbaum J, Saraiva MJ : Transthyretin Ser6 as a neutral polymorphism in familial amyloidotic polyneuropathy. Amyloid Int J Exp Clin Investig 1996; 3: 242–244.
Cooper DN, Smith BA, Cooke HJ, Niemann S, Schmidtke J : An estimate of unique DNA sequence heterozygozity in the human genome. Hum Genet 1985; 69: 201–205.
Li WH, Sadler LA : Low nucleotide diversity in man. Genetics 1991; 129: 513–523.
Almeida MR, Aytama-Oishi N, Sakaki Y et al: Haplotype analysis of common transthyretin mutations. Hum Genet 1995; 96: 350–354.
Plante-Bordeneuve V, Lalu T, Misrahi M et al: Genotypic–phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. Neurology 1998; 51: 708–714.
Cavalli-Sforza L, Menozzi P, Plazza A : The History and Geography of Human Genes. Princeton University Press, Princeton, New Jersey, 1994.
Acknowledgements
We thank Dr Rosário Santos from the Instituto de Genética Médica Jacinto Magalhães for the Portuguese control DNA samples, Paul Moreira for his expertise in DNA diagnosis of the V30M mutation, and Isabel Friães and Laurinda Teixeira for their assistance in collecting blood samples. We also appreciated the review of the manuscript by Drs Jim Koziol and Ernest Beutler of the Department of Molecular and Experimental Medicine at TSRI, and acknowledge the statistical assistance of Dr Chris Amos, MD Anderson Hospital, Houston, TX. Miguel Soares was recipient of a fellowship (PRAXIS XXI, BD/11564/97) from Fundação para a Ciência e Tecnologia, Portugal. Grants from the NIH (R01 AG19259 to JB), the Fundação para Ciência e Tecnologia (to MJS) and the Swedish Medical Research Council (Project 0945 to GH) supported this work.
Author information
Authors and Affiliations
Corresponding author
Additional information
TTR accession numbers: GenBank M11518; GDB 119471; MIM 176300.
Rights and permissions
About this article
Cite this article
Soares, M., Coelho, T., Sousa, A. et al. Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype–phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden. Eur J Hum Genet 12, 225–237 (2004). https://doi.org/10.1038/sj.ejhg.5201095
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5201095
Keywords
This article is cited by
-
Racial and Ethnic Disparities in Transthyretin Cardiac Amyloidosis
Current Cardiovascular Risk Reports (2021)
-
A Descriptive Analysis of ATTR Amyloidosis in Spain from the Transthyretin Amyloidosis Outcomes Survey
Neurology and Therapy (2021)
-
Characteristics of Patients with Late- vs. Early-Onset Val30Met Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS)
Neurology and Therapy (2021)
-
Cellular secretion and cytotoxicity of transthyretin mutant proteins underlie late-onset amyloidosis and neurodegeneration
Cellular and Molecular Life Sciences (2020)
-
Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis
European Journal of Human Genetics (2017)
