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Nucleotide in adenine -> nucleotide in guanine

Gene - sequence of nucleotides that contains information for the construction of a definite protein

Nucleotide - structural unit of the nucleic acids.

Aminoacid - structural unit of proteins.

Amyloid fibrils result from a mutation on the long arm of chromosome 18 of the gene encoding transthyretin (TTR).
The substitution, in this gene, of a single nucleotide in adenine for one in guanine (the bases of nucleotides) at position 30, originates aminoacid methionine (MET) instead of valine, which results in a protein with different characteristics.
As it is dominant, if the individuals are homozygotic (have both elements of the pair chromosome 18 with mutation) they have 100% probability of transmitting the disease to their descendants. If they are heterozygotic (only one of the chromosomes is affected) probability drops to 50 %. Being either homo or heterozygotic does not seem to aggravate the symptoms, as there are cases of assymptomatic homozygotes.


Whereas normal TTR is soluble in plasma and stable in tissues, mutant is soluble in plasma but unstable in the tissues, polymerising and forming amyloid fibrils.

When examined in the polarising microscope, fibrils look greenish, due to the double refraction of incident light.

Deposition of amyloid on a FAP tissue examined in the polarizing microscope.
(Amyloid Unit, IMCB, Rui Fernandes)

As there are other proteins capable of polymerizing, when the researchers examine amyloid deposits in tissues and want to make sure it is TTR, they colour them with antibodies specific to that protein, obtained after injecting TTR into an animal that recognises it as a different protein.

Location of TTR deposits on muscular tissue coloured with antibodies.
(Amyloid Unit, IMBC, Rui Fernandes)

TTR is a tetrameric protein (composed of four subunits) related to the transport of RBP (Rethinol Binding Protein) lipids and thyroxin ( the thyroid gland hormone). If the individual is homozygotic, he has the four mutated subunits, if he is heterozygotic he may have one, two or three. However, if the mechanism of the fibre deposition is the same, which is still being investigated, it does not matter whether he is homo or heterozygotic.
There are other TTR mutations, some of which non-pathogenic, that are associated with MET 30. Six families with double mutation (MET30 and Met 119) have been identified in our country and it has been found that they presented a later onset and a slower progression of the disease. According to Maria Joćo Saraiva, the protection given by the second mutation (Met 119) to the clinical symptoms is due to the fact that fibrils will not be formed unless TTR dissociates into its four subunits. As MET 30 does it more easily and MET 119 offers great resistance to that separation , the association of both mutations weakens symptoms.

© Pedro Soares 2002 | Updated: 10/15/2002