transthyretin-associated amyloidosis
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Transthyretin (TTR) is a homotetrameric protein with a prominent beta-sheet secondary structure. Approximately 80 different mutations in transthyretin have been reported. A few mutations are not associated with amyloidosis, and a couple are thought to protect against the deposition of amyloid.
Transthyretin (TTR), a transport protein for thyroxine and retinol-binding protein, is primarily synthesized in the liver but is also produced in the choroid plexus.
Pathology
In the familial amyloidosis, the substitution of a single amino acid transforms a normal protein into an amyloidogenic one; prototypical proteins are transthyretin (TTR) and lysozyme (LYZ).
More than 50 different substitutions of single amino acids in transthyretin cause familial amyloidotic polyneuropathy. The most common are a substitution of methionine for valine at position 30 (Met 30), which occurs in persons of almost every racial and ethnic background, and alanine for threonine at position 60 (Ala 60), occurring in persons of English and Irish ancestry.
Recently, a unique form of cardiac amyloidosis has been described in which isoleucine is substituted for valine at position 122 (Ile 122).
The importance of the Ile 122 variant lies in the observation that 3.9 percent of the black population carry the mutant gene (allele frequency of 0.02).
Cardiomyopathy due to Ile 122 amyloidosis has been described in homozygous and heterozygous patients, but its prevalence is unknown owing to the almost certain fact that it is underdiagnosed because of the lack of awareness by physicians.
Although the transthyretin mutations are inherited in an autosomal dominant fashion, studies of Met 30 have demonstrated that the age of onset appears to vary according to racial or ethnic group and that about 10 percent of gene carriers never have symptoms.
This observation suggests that other genetic or environmental factors may have a role in the phenotypic expression of these diseases.