Implications of heavy chain disease protein for multiple gene theories of immunoglobulin synthesis

Abstract

The sequence of the amino-terminal 34 amino acids of 'y-heavy chain disease (y-HCD) protein Hi is homologous with the amino-terminal region of immunoglobulin heavy chains. 7-heavy chain disease is smaller than a normal y-chain, but has the carboxy-terminal composition expected for 7y-chains and must, therefore, contain an internal deletion. Comparison of the Hi sequence with that of y-heavy chain disease Zu, which also has an internal deletion, indicates that the site of internal deletion is not a constant characteristic of 7-heavy chain disease proteins. Heavy chains can be assigned to subgroups on the basis of variable region sequences. The variable regions of Hi and one other protein differ significantly from those determined for other heavy chains, and these two proteins are assigned to a new heavy chain variable region subgroup, VHIV. It has been suggested that single immunoglobulin heavy chains are the products of two separate structural genes and that variable region genetic information is translocated and integrated into common region information. These multiple gene theories make no prediction as to whether DNA or RNA is translocated. 7y-heavy chain disease proteins provide unique information that indicates that if translocation is required for the production of immunoglobulin heavy chains, it is DNA, not RNA, that is translocated. Introduction. Heavy chain disease (HCD) proteins are aberrant forms of human immunoglobulin heavy polypeptide chains. Examples of heavy chain disease proteins have been described for the classes IgG,1-7 IgA,8'9 and IgM.10 Studies of IgG HCD (y-HCD) proteins have shown that they consist of portions of the y-chain and that they lack light polypeptide chains. The two 7y-HCD proteins for which data are available have molecular weights of 26,00011 and 40,0007 as compared with a molecular weight of approximately 54,000 for normal 7-chains.12 The structure of y-HCD proteins is of interest because, at least in some cases, they appear to be the intact products of mutated immunoglobulin structural genes, rather than the partially degraded products of normal immunoglobulin structural genes. It was first shown by Prahl3 that the amino acid sequence of the amino-terminal (N-terminal) tripeptide of 7-HCD Zu was similar to the sequence determined for the amino-terminus of 7-chains.'4 Moreover, it was