Human lysozyme gene mutations cause hereditary systemic amyloidosis

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 gene2,3 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.

[1]  C. Pace,et al.  Contribution of hydrogen bonding to the conformational stability of ribonuclease T1. , 1992, Biochemistry.

[2]  M. Skinner,et al.  New USA Family has Apolipoprotein AI (ARG26) Variant , 1991 .

[3]  K. Sletten,et al.  Amyloid and Amyloidosis 1990 , 1991, Springer Netherlands.

[4]  A. E. Sippel,et al.  The human lysozyme gene. Sequence organization and chromosomal localization. , 1989, European journal of biochemistry.

[5]  B. Matthews,et al.  Temperature-sensitive mutations of bacteriophage T4 lysozyme occur at sites with low mobility and low solvent accessibility in the folded protein. , 1987, Biochemistry.

[6]  G. Johnson Immunocytochemistry: 2nd edn , 1980 .

[7]  P. Talmud,et al.  Rapid screening for specific mutations in patients with a clinical diagnosis of familial hypercholesterolaemia. , 1991, Atherosclerosis.

[8]  B. Matthews,et al.  Structural and thermodynamic analysis of compensating mutations within the core of chicken egg white lysozyme. , 1993, The Journal of biological chemistry.

[9]  M. Pepys,et al.  Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. , 1990, The New England journal of medicine.

[10]  P. Hawkins,et al.  Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  P J Artymiuk,et al.  Refinement of human lysozyme at 1.5 A resolution analysis of non-bonded and hydrogen-bond interactions. , 1981, Journal of molecular biology.

[12]  D. Koch,et al.  Surgical management of advanced ocular adnexal amyloidosis. , 1992, Archives of ophthalmology.

[13]  K. Mullis,et al.  Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. , 1988, Science.

[14]  R. Thompson,et al.  CTAB precipitation of cestode DNA. , 1987, Parasitology today.

[15]  Kathryn E. Sidman,et al.  The protein identification resource (PIR). , 1986, Nucleic acids research.

[16]  N. Athanasou,et al.  Localized deposition of amyloid in articular cartilage , 1992, Histopathology.

[17]  M. Pras,et al.  The characterization of soluble amyloid prepared in water. , 1968, The Journal of clinical investigation.

[18]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[19]  V. Turk,et al.  22 – Structure and Chemistry of Lysozyme: pH-Rate Profile, Calorimetric Studies, and Computations on Exposure to Solvent* , 1974 .

[20]  M. Waterfield,et al.  Accelerated high‐sensitivity microsequencing of proteins and peptides using a miniature reaction cartridge , 1992, Protein science : a publication of the Protein Society.

[21]  D. F. Koenig,et al.  Structure of Hen Egg-White Lysozyme: A Three-dimensional Fourier Synthesis at 2 Å Resolution , 1965, Nature.

[22]  J. L. Casanova,et al.  Optimal conditions for directly sequencing double-stranded PCR products with sequenase , 1990, Nucleic Acids Res..

[23]  M. Waterfield,et al.  Identification of a novel autophosphorylation site (P4) on the epidermal growth factor receptor. , 1989, The Biochemical journal.

[24]  A. Fleming On a Remarkable Bacteriolytic Element Found in Tissues and Secretions , 1922 .

[25]  D. Phillips,et al.  Crystallographic studies of the dynamic properties of lysozyme , 1979, Nature.

[26]  H. Puchtler,et al.  ON THE BINDING OF CONGO RED BY AMYLOID , 1962 .