Faculty Bibliography

Amyloidosis constitutes a group of diseases in which extracellular fibrils with a characteristic appearance are deposited in a variety of tissues. Several different proteins have been identified as the major subunits of the fibrils. In the primary and myeloma-associated type, the amyloid fibrils consist of immunoglobulin light chain fragments, whereas in the secondary type and the amyloid associated with familial Mediterranean fever the major component is the AA protein. In this report a 21 year old man of Yemenite extraction with no underlying disease and no family history of amyloidosis was found to have amyloid deposits composed of AA protein. Although clinically this might be classified as primary amyloidosis, the absence of light chain fragments makes that diagnosis unlikely. Therefore, it is suggested that whenever possible the clinical classification be supplemented by a description of the biochemical nature of the fibrils.

A gamma l heavy-chain disease protein (EST) is described which lacks the entire VH and CHl domains and starts with the normal sequence of gamma l H-chains corresponding to the beginning of the hinger region (position 216). Although degradation cannot be excluded with certainty, it is probable that this protein is synthesized as an internally deleted gamma heavy-chain disease protein. Presumably a DNA recombination has occurred resulting in the deletion of the genes of coding for the VH and CHl domains with splicing of the precursor RNA to the sequence coding for the hinge region.

It is generally accepted that the variable (V) and constant (C) regions of immunoglobulin (Ig) chains are under separate genetic control. The notion that the different domains and interdomain regions are also under the control of independent genetic units was initially based on the clearcut results obtained by studying the primary structure of deletion mutants and received definitive support from direct analysis of cloned heavy (H) and light (L) chain genes. Here we present additional studies carried out on two selected gamma 3 deletion mutants which indicate the genetic control of human H chains may be even more complex than previously believed.

The gelatin-binding region of fibronectin has been obtained by subtilisin digestion and cyanogen bromide cleavage of the molecule. Enzymatic digestion yielded two fragments of molecular weights 50,000 (S50K) and 30,000 (S30K) which were isolated by elution from gelatin-Sepharose affinity columns. Because the S50K fragment also mediated the adhesion of fibroblasts to collagen, it contains both the collagen and cell binding sites on the fibronectin molecule. Both fragments had valine as the NH2-terminal residue, were enriched in half-cystine and methionine residues compared to the whole molecule, and were identical by immunodiffusion. The S50K fragment begins with the sequence Val-Tyr-Gln-Pro-Gln-Pro-His-Pro-Gln-Pro-(Pro)-(Gly)-Tyr-Gly-His-( )-Val, a region with an extended conformation which is susceptible to proteolysis and connects this domain to the remainder of the fibronectin molecule. The S50K fragment appears to be located in the COOH-terminal one-third of the fibronectin molecule but does not contain the interchain disulfide bridge(s); the S30K fragment is probably derived from the NH2-terminal region of S50K.