TTR (transthyretin; HGNC:12405, NCBI Gene ID 7276) is a human locus mapped to chromosome band 18q12.1 that encodes homotetrameric beta-sheet plasma carrier protein Transthyretin (127 mature aa per monomer; 55 kDa tetramer). TTR acts in plasma & CSF transport of thyroxine (T4) and retinol-binding protein 4 (RBP4), together with Small Interfering RNA (siRNA), CRISPR-Cas9 Genome Editing, and Guide RNA (gRNA / sgRNA). Encodes transthyretin, the hepatic tetrameric transporter of thyroxine and retinol whose dissociation causes hereditary and wild-type ATTR amyloidosis.
Approved Symbol
TTR
Chromosomal Locus
18q12.1
Encoded Product
Homotetrameric beta-sheet plasma carrier protein Transthyretin (127 mature aa per monomer; 55 kDa tetramer)
Primary Pathway
Plasma & CSF transport of thyroxine (T4) and retinol-binding protein 4 (RBP4)
Genomic Organization & Cytogenetic Locus: 4-exon compact gene spanning ~7 kb on chromosome 18q12.1, encoding a 147-amino-acid preprotein (127-residue mature monomer rich in beta-strands A through H) that assembles as a dimer of dimers creating two funnel-shaped central hydrophobic thyroxine-binding channels.
Cellular & Tissue Expression Profile: Synthesized at massive levels by hepatic hepatocytes (which secrete >95% of circulating plasma TTR) and independently by the choroid plexus epithelium of the brain ventricles (into cerebrospinal fluid) and retinal pigment epithelium.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Transports thyroid hormone thyroxine (T4) in cerebrospinal fluid and plasma while forming a macromolecular complex with holo-retinol-binding protein (RBP4-vitamin A) that prevents glomerular filtration of RBP4; rate-limiting dissociation of the native TTR tetramer into partially unfolded monomers triggers cross-beta amyloid fibril self-assembly in peripheral nerves and myocardium.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Over 130 autosomal dominant missense mutations destabilize the TTR tetramer and cause hereditary transthyretin amyloidosis (ATTRv): p.Val30Met (p.Val50Met) predominantly causes familial amyloid polyneuropathy, whereas p.Val122Ile (p.Val142Ile, carried by ~3–4% of African Americans) causes late-onset restrictive amyloid cardiomyopathy; conversely, the suppressor mutation p.Thr119Met (p.Thr139Met) hyperstabilizes the tetramer, while age-related dissociation of unmutated TTR causes wild-type cardiac amyloidosis (ATTRwt).
Therapeutic & Clinical Pharmacology: The flagship clinical proof-of-concept locus for nearly every modern therapeutic modality: kinetic tetramer stabilizers (tafamidis, acoramidis, inspired by the protective Thr119Met allele), the first FDA-approved siRNA drug, LNP-formulated patisiran (Onpattro) and GalNAc-siRNA vutrisiran (Amvuttra), antisense oligonucleotides inotersen and eplontersen (Wainua), and nexiguran ziclumeran (NTLA-2001), a systemic LNP-CRISPR-Cas9 therapy demonstrating ~90% durable TTR knockdown in humans after a single intravenous infusion.