The hereditary form of amyloidosis, familial amyloidotic polyneuropathy (FAP) is an autosomal dominantly inherited condition associated with a mutant form of the protein transthyretin (TTR, also called pre-albumin). It is a rare late-onset genetic disease which results in rapid deterioration due to peripheral and autonomic neuropathy and cardiomyopathy in the third or fourth decade of life. It raises the question of how an abnormal gene which is present from birth produces disease a decade later. Biopsies have proven that amyloid deposition begins just prior to the time of first symptoms. Six variant forms of the amyloid precursor TTR had been identified. Each involves a single amino acid substitution in the normal 127 amino acid chain of TTR. In their population of patients from 28 families with FAP, the applicants have recently identified one new variant and have other families with variants of unknown type. They differ phenotypically and in ethnic origin from each other and do not have one of the known TTR variants. The applicants proposed to examine their DNA and/or plasma for TTR variations that have resulted in amyloid deposition and to determine techniques for the genetic testing of that mutation. One patient with a homozygous mutant pattern will provide the unique opportunity to examine its proteolysis and to develop an antibody only to the mutant protein. They plan to test the hypothesis that variations in clinical symptoms, age at onset, and disease progression may be explained by factors other than the single nucleotide mutation in the TTR gene. Their preliminary data suggest a radical change in the beta formation of the mutant TTR when digested with a proteolytic enzyme human neutrophil elastase. These studies will be extended to TTR proteins from individuals who have pre-symptomatic FAP and carried out on known proportions of normal and variant TTR in the isolated mixture. Understanding the pathogenetic mechanisms involved in the processing of the precursor TTR into amyloid fibrils, they anticipate, will aid in the ultimate goal of defining treatment intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR040414-04
Application #
2080041
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1991-02-01
Project End
1996-01-31
Budget Start
1994-02-01
Budget End
1996-01-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Falk, R H; Skinner, M (2000) The systemic amyloidoses: an overview. Adv Intern Med 45:107-37
Theberge, R; Connors, L H; Skinner, M et al. (2000) Detection of transthyretin variants using immunoprecipitation and matrix-assisted laser desorption/ionization bioreactive probes: a clinical application of mass spectrometry. J Am Soc Mass Spectrom 11:172-5
Theberge, R; Connors, L; Skinner, M et al. (1999) Characterization of transthyretin mutants from serum using immunoprecipitation, HPLC/electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry. Anal Chem 71:452-9
Connors, L H; Ericsson, T; Skare, J et al. (1998) A simple screening test for variant transthyretins associated with familial transthyretin amyloidosis using isoelectric focusing. Biochim Biophys Acta 1407:185-92
Falk, R H; Comenzo, R L; Skinner, M (1997) The systemic amyloidoses. N Engl J Med 337:898-909
Bergethon, P R; Sabin, T D; Lewis, D et al. (1996) Improvement in the polyneuropathy associated with familial amyloid polyneuropathy after liver transplantation. Neurology 47:944-51
Campistol, J M; Bernard, D; Papastoitsis, G et al. (1996) Polymerization of normal and intact beta 2-microglobulin as the amyloidogenic protein in dialysis-amyloidosis. Kidney Int 50:1262-7
Skinner, M; Anderson, J; Simms, R et al. (1996) Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 100:290-8
Dubrey, S; Pollak, A; Skinner, M et al. (1995) Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Br Heart J 74:541-4
Skinner, M; Lewis, W D; Jones, L A et al. (1994) Liver transplantation as a treatment for familial amyloidotic polyneuropathy. Ann Intern Med 120:133-4

Showing the most recent 10 out of 17 publications