title: A novel transthyretin variant p.H110D (H90D) as a cause of familial amyloid polyneuropathy in a large Irish kindred.
abstract: Hereditary transthyretin (ATTR) amyloidosis is caused by inheritance of an abnormal TTR gene in an autosomal dominant fashion. In its native state, TTR is a homotetramer consisting of four identical polypeptides. Mutations in the TTR gene contribute to destabilization and dissociation of the TTR tetramer, enabling abnormally folded monomers to self-assemble as amyloid fibrils. Currently, over 120 TTR variants have been described, with varying geographic distributions, degrees of amyloidogenicity and organ involvement. We report here a large Irish family with familial amyloid polyneuropathy (FAP), consisting of multiple affected generations, caused by a novel TTR mutation; p.H110D (H90D). The demonstration, by immunohistochemistry and laser micro dissection-mass spectrometry (LMD/MS) that the amyloid fibrils were composed of TTR, in conjunction with a typical FAP phenotype, indicates that the novel TTR mutation was the cause of amyloidosis. We used a molecular visualization tool PyMOL to analyze the effect of the p.H110D (H90D) replacement on the stability of the TTR molecule. Our data suggest that the loss of two hydrogen bonds and the presence of an additional negative charge in the core of a cluster of acidic residues significantly perturb the tetramer stability and likely contribute to the pathogenic role of this variant.
authors.affiliation: Department of Medical Oncology and Hematology, Tom Baker Cancer Center , Calgary, AB , Canada and.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Jimenez-Zepeda
authors.forename: Nizar J
authors.initials: NJ
authors.lastname: Bahlis
authors.forename: Janet
authors.initials: J
authors.lastname: Gilbertson
authors.forename: Nigel
authors.initials: N
authors.lastname: Rendell
authors.forename: Riccardo
authors.initials: R
authors.lastname: Porcari
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Lachmann
authors.forename: Julian D
authors.initials: JD
authors.lastname: Gillmore
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Dorota M
authors.initials: DM
authors.lastname: Rowczenio
mesh_terms: D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000175:diagnosis* / Q000235:genetics; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007494:Ireland; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D011228:Prealbumin / Q000235:genetics*
chemical_list: D011228:Prealbumin
keywords: Amyloidosis; familial amyloid polyneuropathy; hereditary transthyretin amyloidosis