TTR Introduction

TABULATION OF TRANSTHYRETIN (TTR) VARIANTS

The past 10 years have been a remarkable period of discovery in the study of familial amyloidotic polyneuropathy (FAP), a disease associated with the plasma protein transthyretin (TTR). Since TTR was first identified in the extracellular deposits of patients with hereditary amyloidosis more than two decades ago, there have been an extraordinary number of reports detailing the existence of over 80 variant forms of the protein. It is quite remarkable that more than 30 of these variants have been identified within the past four years; the current rate of discovery suggests that many more mutations will be reported, as improved analytical methods are applied to the quest and as a wider patient population gains access to appropriate diagnostic services.
While the vast majority of the reported TTR mutations are amyloidogenic, the precise cause(s) and mechanism(s) responsible for aberrant TTR subunit assembly (or misassembly) into amyloid fibrils remains undetermined. The genetic basis of the disease stems from single base nucleotide mutations that occur throughout the entire coding region of the TTR gene. The phenotypes of TTR-associated familial amyloidosis are varied, but common clinical features and ethnic origins have been noted among kinships afflicted with identical TTR mutations.

This collection should facilitate the work of laboratory investigators and provide a guide to the literature for those who wish to gain familiarity with the field. TTR proteins are presented in tabular form, listed in ascending order according to the position of the variant amino acid. As is customary, the three-letter code for the residue present in the wild type protein appears on the left, followed by the position number and the three-letter code for the variant amino acid, e.g., Cys10Arg indicates that the residue cysteine (Cys) at position 10 is replaced by arginine (Arg) in the mutant protein. The corresponding genetic, biochemical, clinical and demographic information (as currently available) is summarized for each variant. Specifically, genetic mutation data (DNA base change) and resultant amino acid mass shifts (change in amino acid residue mass between wild type and variant at the position where the base substitution occurs) are listed. For the amyloidogenic variants, clinical features (phenotype) and world-wide distribution (geographic focus/ethnic origin) are detailed. Non-amyloidogenic proteins are shown in italicized print. The earliest report of the gene or protein mutation appears in the table of mutations. A comprehensive list of initial and subsequent references to each variant and major reviews on TTR polymorphisms is also included as a separate table containing the complete literature citations.

The online information is being updated regularly. Recently. another TTR database has been established by Maria Saraiva In order to maintain the universality of coverage in the database as new mutations are discovered, investigators are encouraged to furnish copies of reports when they are published or accepted for publication, sending them by post or by e-mail to the BUSM MS Resource (to C. E. Costello, cecmsms@bu.edu) and to Maria Saraiva (mjsaraiv@ibmc.up.pt).