Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I

Dorota Rowczenio, Ahmet Dogan, Jason D. Theis, Julie A. Vrana, Helen J. Lachmann, Ashutosh D. Wechalekar, Janet A. Gilbertson, Toby Hunt, Simon D J Gibbs, Prayman T. Sattianayagam, Jenny H. Pinney, Philip N. Hawkins, Julian D. Gillmore

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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 spectrometrybased 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.

Original languageEnglish (US)
Pages (from-to)1978-1987
Number of pages10
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
StatePublished - Oct 2011

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Apolipoprotein A-I
Amyloidosis
Phenotype
Mutation
Amyloid
Amyloidogenic Proteins
Microdissection
Proteins
Amyloid Plaques
Proteomics
Chronic Kidney Failure
Young Adult
Lasers
Light
Drug Therapy
Skin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Rowczenio, D., Dogan, A., Theis, J. D., Vrana, J. A., Lachmann, H. J., Wechalekar, A. D., ... Gillmore, J. D. (2011). Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. American Journal of Pathology, 179(4), 1978-1987. https://doi.org/10.1016/j.ajpath.2011.06.024

Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. / Rowczenio, Dorota; Dogan, Ahmet; Theis, Jason D.; Vrana, Julie A.; Lachmann, Helen J.; Wechalekar, Ashutosh D.; Gilbertson, Janet A.; Hunt, Toby; Gibbs, Simon D J; Sattianayagam, Prayman T.; Pinney, Jenny H.; Hawkins, Philip N.; Gillmore, Julian D.

In: American Journal of Pathology, Vol. 179, No. 4, 10.2011, p. 1978-1987.

Research output: Contribution to journalArticle

Rowczenio, D, Dogan, A, Theis, JD, Vrana, JA, Lachmann, HJ, Wechalekar, AD, Gilbertson, JA, Hunt, T, Gibbs, SDJ, Sattianayagam, PT, Pinney, JH, Hawkins, PN & Gillmore, JD 2011, 'Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I', American Journal of Pathology, vol. 179, no. 4, pp. 1978-1987. https://doi.org/10.1016/j.ajpath.2011.06.024
Rowczenio, Dorota ; Dogan, Ahmet ; Theis, Jason D. ; Vrana, Julie A. ; Lachmann, Helen J. ; Wechalekar, Ashutosh D. ; Gilbertson, Janet A. ; Hunt, Toby ; Gibbs, Simon D J ; Sattianayagam, Prayman T. ; Pinney, Jenny H. ; Hawkins, Philip N. ; Gillmore, Julian D. / Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. In: American Journal of Pathology. 2011 ; Vol. 179, No. 4. pp. 1978-1987.
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