title: Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.
abstract: We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis.
authors.affiliation: Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
authors.forename: D R
authors.initials: DR
authors.lastname: Booth
authors.forename: S Y
authors.initials: SY
authors.lastname: Tan
authors.forename: S E
authors.initials: SE
authors.lastname: Booth
authors.forename: G A
authors.initials: GA
authors.lastname: Tennent
authors.forename: W L
authors.initials: WL
authors.lastname: Hutchinson
authors.forename: J J
authors.initials: JJ
authors.lastname: Hsuan
authors.forename: N F
authors.initials: NF
authors.lastname: Totty
authors.forename: O
authors.initials: O
authors.lastname: Truong
authors.forename: A K
authors.initials: AK
authors.lastname: Soutar
authors.forename: P N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: M
authors.initials: M
authors.lastname: Bruguera
authors.forename: J
authors.initials: J
authors.lastname: Caballería
authors.forename: M
authors.initials: M
authors.lastname: Solé
authors.forename: J M
authors.initials: JM
authors.lastname: Campistol
authors.forename: M B
authors.initials: MB
authors.lastname: Pepys
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016632:Apolipoprotein A-I / Q000235:genetics*; D001483:Base Sequence; D005260:Female; D006801:Humans; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D000683:Serum Amyloid P-Component / Q000032:analysis
chemical_list: D016632:Apolipoprotein A-I; D000683:Serum Amyloid P-Component