Human lysozyme gene mutations cause hereditary systemic amyloidosis

Abstract

HEREDITARY non-neuropathic systemic amyloidosis (Ostertag-type)¹ is a rare autosomal dominant disease in which amyloid deposition in the viscera is usually fatal by the fifth decade. In some families it is caused by mutations in the apolipoprotein AI gene^2,3 but in two unrelated English families under our care the amyloid deposits did not contain apoAI, despite a report that this may have been the case in one of them⁴. Lysozyme is a ubiquitous bacteriolytic enzyme present in external secretions⁵ and in poly-morphs and macrophages, but its physiological role is not always clear⁶. Here we report that in these two families, lysozyme is the amyloid fibril protein. Affected individuals are heterozygous for point mutations in the lysozyme gene that cause substitution of highly conserved residues, namely threonine for isoleucine at position 56 in one family, and histidine for aspartic acid at residue 67 in the other. Amyloid fibrils from one individual were composed of the full-length Thr-56 variant lysozyme molecule. To our knowledge, this is the first report of naturally occurring variants of human lysozyme and of lysozyme-associated disease. As the structures of human⁷ and hen egg-white lysozyme⁸ are known to atomic resolution and their folding and structure–function relationships have been exhaustively analysed, our observations should provide a powerful model for understanding amyloidogenesis.