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Genetic factors in the amyloid diseases

Author
Peter D Gorevic, MD
Section Editors
Peter H Schur, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Paul L Romain, MD

INTRODUCTION

Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils composed of low molecular weight subunits (5 to 25 kD) of proteins, many of which are normal constituents of serum. The fibrils are insoluble polymers comprised of these low molecular weight subunit proteins. These subunits are derived, in turn, from soluble precursors, which undergo conformational changes that lead to the adoption of a predominantly antiparallel beta-pleated sheet configuration [1,2].

Amyloid deposits appear as amorphous hyaline material on light microscopy (picture 1A-D). The fibrils bind Congo red (leading to green birefringence under polarized light) and thioflavine T (producing an intense yellow-green fluorescence). Electron microscopic examination of the ultrastructure of amyloid deposits generally demonstrates straight and unbranching fibrils, which may be composed of protofilaments at higher resolution [3]. Immunohistochemical [4] and biochemical [5] techniques can be used to identify the type of protein subunit.

Routes to fibrillogenesis include partial folding or unfolding of the precursor protein that may be facilitated by acidification or proteolysis and that may be accelerated by nucleation [6-9]. Fibril formation is also associated with co-deposition of other substances, notably including glycosaminoglycans (GAGs, particularly heparan sulfate), serum amyloid P-component (SAP, a member of the pentraxin family that includes C-reactive protein), and specific apolipoproteins (E and J) [10-12]. Cofactors, including molecular chaperones and proteases, may significantly modulate fibrillogenesis at any of several steps involved in the conversion of soluble precursors to fibrils and may potentially influence the deposition phase of amyloid in tissue, as well as resorption [13-15].

The importance of heredity in the expression of amyloid diseases has been recognized for many years [16]. Some amyloid disorders appear to be entirely due to heritable abnormalities in precursor proteins. In addition, the expression of acquired amyloidoses may be affected by genetically determined factors.

The genetic contributions to various types of amyloidosis will be reviewed here. Three types of genetic abnormalities have been identified in amyloidogenic proteins: polymorphisms, variant molecules (eg, due to missense mutations, deletions, or premature stop codons), and genetically determined posttranslational modifications (table 1). In addition, mutations in genes for non-amyloidogenic proteins can play a permissive role in amyloid development. Examples include pyrin mutations in familial Mediterranean fever and presenilin mutations in early-onset Alzheimer disease.

                         

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Literature review current through: Nov 2016. | This topic last updated: Tue Jul 19 00:00:00 GMT+00:00 2016.
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