title: Identification of a novel transthyretin Thr59Lys/Arg104His. A case of compound heterozygosity in a Chinese patient diagnosed with familial transthyretin amyloidosis.
abstract: Transthyretin (TTR) is a 127-amino acid residue protein synthesized mainly in the liver and in several minor sites, including the choroid plexus and the eye. In plasma, TTR circulates as a homotetramer and transports the hormone thyroxine and the retinol-binding protein-vitamin A complex. It is hypothesized that amino acid substitutions in TTR destabilize the tetramer by causing each subunit toform intermediates that may self-associate into amyloid fibrils. Deposition of wild type TTR, its variants and/or fragments as amyloid fibrils in tissues and organs is associated with familial transthyretin amyloidosis (ATTR). Reported herein is the characterization of a novel TTR Thr59Lys/Arg104His in a patient of Chinese ancestry, who was diagnosed with ATTR. The two variant proteins and the double gene mutations in this compound heterozygous case were detected and identified using a multifaceted approach consisting of isoelectric focusing, electrospray ionization mass spectrometry (MS), matrix-assisted laser desorption/ionization time-of-flight MS in combination with enzymatic digestion, and direct DNA sequence analysis. Previous studies have shown that the TTR Arg104His variant is non-pathologic. It appeared to provide a protective effect in another compound heterozygous case (TTR Val30Met/Arg104His). However, the TTR Arg104His variant when presented with the TTR Thr59Lys variant did not seem to have any protective role.
authors.forename: Amareth
authors.initials: A
authors.lastname: Lim
authors.forename: Tatiana
authors.initials: T
authors.lastname: Prokaeva
authors.forename: Lawreen H
authors.initials: LH
authors.lastname: Connor
authors.forename: Rodney H
authors.initials: RH
authors.lastname: Falk
authors.forename: Martha
authors.initials: M
authors.lastname: Skinner
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
mesh_terms: D019943:Amino Acid Substitution; D028226:Amyloidosis, Familial / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D044466:Asian People; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D007525:Isoelectric Focusing; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011228:Prealbumin / Q000235:genetics*; D017422:Sequence Analysis, DNA; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D017931:DNA Primers; D011228:Prealbumin