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New clues to amyloidoses ? (02/2005)

Familial amyloid polyneuropathy  (FAP), a hereditary disease characterised by abnormal deposits of insoluble protein in the organs, results from a mutation in a single gene (the transthyretin or TTR gene). Nevertheless, disease incidence and age of onset can vary significantly between patients what have always puzzled scientists. Now, in the latest issue of the journal Human Molecular Genetics1, a team of researchers propose for the first time that other genes might be involved in the clinical signs of FAP what would exxplain why patients with a single TTR mutation can, nevertheless, have such different disease.

Amyloidoses are diseases where normally soluble proteins form insoluble deposits (amyloids) causing organ damage and many times patient death.  Examples include Alzheimer’s disease and Creutzfeldt-Jakob Disease or CJD (the human variant of mad cow disease) and also familial amyloid polyneuropathy or FAP.  FAP was been first described in 1939 in the Portuguese population and is believed to have been spread by Portuguese sailors to Sweden and Japan, and from there to the rest of the world. The condition results from a mutation in the gene coding for transthyretin (TTR), a human plasma protein, that becomes insoluble creating the particular amyloids of FAP.

Although FAP is provoked by a single gene mutation, symptoms and disease mortality vary enormously among patients.  Portuguese sufferers, for example, tend to have an early disease onset (around 20-35 years of age) and an extremely severe disease with multiple organs affected, including peripheral nerves, kidney, heart, stomach and the small intestine. Patients tend to die within 10 years although some might last less than 2 years. In Sweden, on the other hand, the majority of patients have a much later disease onset, usually after the age of 50, and a much slower disease progression. Such variations have made scientists believe that other factors, such as the environment or additional genes, were also involved in the pathology.

Now Miguel L. Soares, Teresa Coelho, Joel N. Buxbaum and colleagues from research groups in Portugal and the US, in an attempt to understand the variations observed in the disease, studied 92 patients with different severity and age of onset. The team of scientists looked at genes involved either with TTR function (genes coding for proteins that metabolically interact with TTR) or amyloid deposition.  Soares, Coelho, Buxbaum and colleagues’ results seem to indicate that the variability in disease found among different patients originates, not from the action of a particular gene, but from the combined interaction of several genes. The genes proposed to be involved in FAP include the APCS gene, which code for a protein found in the FAP amyloid deposit and the RBP gene which codes for retinol-binding protein, a vitamin A carrier which circulates in the plasma bound to TTR and so it can affect TTR solubility. Interestingly too, it seems that different ages of onset are influenced by distinct sets of genes (in addition to the TTR mutation) almost as independent diseases.

Soares, Coelho, Buxbaum and colleagues’ results are very interesting as, with further studies, they might be used to predict disease and consequently help the treatment of patients with TTR mutation but yet with no symptoms. Their work might also help to understand why elderly individuals, with no mutation in the TTR gene, can, nevertheless, present extended amyloid deposits and suffer the consequently organ damage. Finally, their studies might also contribute to research into the mechanisms behind other amyloidoses such as CJD or Alzheimer’s.


1 Human Molecular Genetics (2005); Vol (14),  pp. 543-533
Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease

Original paper’s author

Joel N. Buxbaum - jbux@scripps.edu
Miguel J. Soares -

Link to the original paper



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