title: Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I.
abstract: The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as "primary"), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Laser microdissection and tandem mass spectrometry-based proteomics were used to confirm the amyloid fibril protein and, for the first time in apolipoprotein A-I amyloidosis, demonstrated that only mutated protein as opposed to wild-type apolipoprotein A-I was deposited as amyloid. The clinical spectrum and outcome of hereditary apolipoprotein A-I amyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease.
authors.affiliation: National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, England.
authors.forename: Dorota
authors.initials: D
authors.lastname: Rowczenio
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.forename: Jason D
authors.initials: JD
authors.lastname: Theis
authors.forename: Julie A
authors.initials: JA
authors.lastname: Vrana
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Lachmann
authors.forename: Ashutosh D
authors.initials: AD
authors.lastname: Wechalekar
authors.forename: Janet A
authors.initials: JA
authors.lastname: Gilbertson
authors.forename: Toby
authors.initials: T
authors.lastname: Hunt
authors.forename: Simon D J
authors.initials: SD
authors.lastname: Gibbs
authors.forename: Prayman T
authors.initials: PT
authors.lastname: Sattianayagam
authors.forename: Jenny H
authors.initials: JH
authors.lastname: Pinney
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Julian D
authors.initials: JD
authors.lastname: Gillmore
mesh_terms: D000328:Adult; D000368:Aged; D000682:Amyloid / Q000378:metabolism; D000686:Amyloidosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D016632:Apolipoprotein A-I / Q000235:genetics*; D001706:Biopsy; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007834:Lasers; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010159:Palate / Q000473:pathology; D010641:Phenotype; D040901:Proteomics; D011877:Radionuclide Imaging; D000683:Serum Amyloid P-Component; D053719:Tandem Mass Spectrometry
chemical_list: C505693:APOA1 protein, human; D000682:Amyloid; D016632:Apolipoprotein A-I; D050505:Mutant Proteins; D000683:Serum Amyloid P-Component