HGNC Approved Gene Symbol: LYZ
Cytogenetic location: 12q15 Genomic coordinates (GRCh38) : 12:69,348,381-69,354,234 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q15 | Amyloidosis, hereditary systemic 5 | 620658 | 3 |
Lysozyme (EC 3.2.1.17) catalyzes the hydrolysis of certain mucopolysaccharides of bacterial cell walls. Specifically, it catalyzes the hydrolysis of the bacterial cell wall beta(1-4) glycosidic linkages between N-acetylmuramic acid and N-acetylglucosamine. It is found in spleen, lung, kidney, white blood cells, plasma, saliva, milk, and tears.
Yoshimura et al. (1988) isolated a cDNA encoding human lysozyme from a human placenta cDNA library. The 1.5-kb cDNA coded for a signal peptide consisting of 18 amino acids and for mature lysozyme. The amino acid sequence of the mature lysozyme, deduced from the nucleotide sequence, was identical to the published sequence. Human lysozyme has 130 amino acid residues and 4 disulfide bonds (Taniyama et al., 1991).
Peters et al. (1989) described the isolation of 2 overlapping genomic clones containing 25 kb of the human lysozyme gene region. They also isolated a full-length human lysozyme cDNA clone from a human placental cDNA library. They reported on the nucleotide sequence of the entire structural gene and the cDNA clone.
Canet et al. (1999) studied the unfolding and refolding properties of human lysozyme and 2 of its amyloidogenic variants, ile56 to thr and asp67 to his, by stopped-flow fluorescence and hydrogen exchange pulse labeling coupled with mass spectrometry. Their results suggested that the amyloidogenic nature of the lysozyme variants arises from a decrease in the stability of the native fold relative to partially folded intermediates. The origin of this instability was different in the 2 variants, being caused in one case primarily by a reduction in the folding rate and in the other by an increase in the unfolding rate. In both cases, this resulted in a low population of soluble partially folded species that can aggregate in a slow and controlled manner to form amyloid fibrils.
Dumoulin et al. (2003) reported that a single-domain fragment of a camelid antibody raised against wildtype human lysozyme inhibited the in vitro aggregation of its amyloidogenic variant, D67H (153450.0002). Structural studies revealed that the epitope includes neither the site of mutation nor most residues in the region of the protein structure that is destabilized by the mutation. Instead, the binding of the antibody fragment achieves its affect by restoring the structural cooperativity characteristic of the wildtype protein. Dumoulin et al. (2003) suggested that this appears to occur at least in part through the transmission of long-range conformational effects to the interface between the 2 structural domains of the protein.
Using a panel of somatic cell hybrids, Peters et al. (1989) assigned the lysozyme gene to human chromosome 12.
Stumpf (2025) mapped the LYZ gene to chromosome 12q15 based on an alignment of the LYZ sequence (GenBank BC004147) with the genomic sequence (GRCh38).
In 2 unrelated English families with hereditary nonneuropathic systemic amyloidosis (AMYLD5; 620658), Pepys et al. (1993) identified heterozygous point mutations in the LYZ gene (I56T, 153450.0001 and D67H, 153450.0002) that segregated with disease.
Gillmore et al. (1999) stated that the English family studied by them and found to be heterozygous for a D67H mutation in the LYZ gene was part of the kindred originally reported by Pepys et al. (1993). They further stated that the family reported by Harrison et al. (1996) also carried the D67H mutation but was apparently unrelated.
In affected members of a French family with autosomal dominant hereditary amyloidosis with early sicca syndrome and nephropathy leading to renal failure, Valleix et al. (2002) identified a heterozygous missense mutation (W64R; 153450.0003) in the LYZ gene.
In affected members of an Italian Canadian family segregating autosomal dominant familial visceral amyloidosis, Yazaki et al. (2003) identified a heterozygous missense mutation (F57I; 153450.0004) in the LYZ gene.
In a 59-year-old woman from Piedmont, Italy, with hereditary lysozyme amyloidosis, mainly characterized by gastrointestinal involvement, Granel et al. (2002) identified heterozygosity for a W64R substitution in the LYZ gene (153450.0005). Granel et al. (2005) identified this same mutation in another woman from Piedmont, and Granel et al. (2006) identified it in an English man. The substitution resulted from a different nucleotide change than the W64R mutation found by Valleix et al. (2002) (153450.0003).
Prieur et al. (1974) described inherited lysozyme deficiency in rabbits. No abnormality of cartilage or bone was noted (Greenwald et al., 1975). Older mutant rabbits showed increased susceptibility to infections, especially subcutaneous abscesses (Prieur, 1975). Camara et al. (1990) identified 2 isozymes of rabbit lysozyme and showed that their distribution was tissue specific. Leukocytic and gastrointestinal isozymes were clearly distinguished, and a possible lymphoepithelial isozyme that resembled the gastrointestinal isozyme electrophoretically and chromatographically but not kinetically was demonstrated. Mutant, lysozyme-deficient rabbits completely lacked a detectable leukocytic isozyme but had gastrointestinal and lymphoepithelial isozymes indistinguishable from those of normal rabbits. By electrophoretic methods, the mutant rabbits were shown to lack a protein band corresponding to that of the leukocytic isozyme in normal rabbits.
Alexander Fleming (1881-1955), of penicillin fame, discovered and named lysozyme. In a communication to the Royal Society, Fleming (1922) wrote: '...I wish to draw attention to a substance present in the tissues and secretions of the body, which is capable of rapidly dissolving certain bacteria. As this substance has properties akin to those of ferments I have called it a Lysozyme....' Fleming and Allison (1922) demonstrated an unusually high concentration in cartilage, indeed the highest of any tissue. It resembles lactalbumin (149750) in structure. Human lysozyme has a molecular mass of 14,602 Da. Neufeld (1972) suggested that a genetic defect of lysozyme might underlie a skeletal dysplasia.
In the proband, the last surviving affected member, of an English family (family 1) with hereditary nonneuropathic systemic amyloidosis (AMYLD5; 620658), Pepys et al. (1993) identified a heterozygous T-to-C transition in exon 2 of the LYZ gene that resulted in an ile56-to-thr (I56T) substitution. An unaffected family member was shown to be homozygous for the wildtype sequence. This family had previously been described by Zalin et al. (1991), who had incorrectly reported that the amyloid deposits contained apolipoprotein A-I (107680), a previously known cause of renal amyloidosis.
In 2 affected members of an English family (family 2) with hereditary nonneuropathic systemic amyloidosis (AMYLD5; 620658), Pepys et al. (1993) identified a heterozygous G-to-G transversion in exon 2 of the lysozyme gene, resulting in an asp67-to-his (D67H) substitution. Four unaffected members were homozygous for the wildtype sequence. The proband of this family had been reported by Lanham et al. (1982).
Gillmore et al. (1999) studied an English family that was part of the kindred originally reported by Pepys et al. (1993), and confirmed the D67H mutation. Affected members in earlier generations presented with renal involvement, frequently developed complications due to gastrointestinal amyloid, and died before age 60 years.
Gillmore et al. (1999) reported that a D67H mutation in the LYZ gene was present in affected members of the family reported by Harrison et al. (1996), in which spontaneous hepatic hemorrhage with rupture of the liver occurred. Gillmore et al. (1999) stated that the family reported by Harrison et al. (1996) and family 2 reported by Pepys et al. (1993) were unrelated.
In affected members of a French family with autosomal dominant hereditary amyloidosis (AMYLD5; 620658), Valleix et al. (2002) identified a T-to-C transition in exon 2 of the LYZ gene, resulting in a tryptophan-to-arginine substitution at codon 64 (W64R). The mutation was not found in 2 unaffected family members or in 80 healthy unrelated individuals.
In an Italian Canadian family segregating autosomal dominant familial visceral amyloidosis (AMYLD5; 620658), Yazaki et al. (2003) identified a T-to-A transversion in exon 2 of the LYZ gene, resulting in a phe-to-ile substitution at residue 57 (F57I). The proband developed renal failure at the age of 42, but a younger sister and daughter also had renal amyloidosis.
In a 59-year-old woman from Piedmont, Italy, with hereditary lysozyme amyloidosis (AMYLD5; 620658), characterized mainly by gastrointestinal involvement, Granel et al. (2002) identified heterozygosity for a T-to-A transition in the LYZ gene, resulting in a W64R substitution.
In a 62-year-old woman from Piedmont, Italy, who was presumably unrelated to the patient reported by Granel et al. (2002), Granel et al. (2005) identified the same T-to-A mutation leading to the W64R substitution. The patient was diagnosed as having systemic digestive and 'medullar' amyloidosis. Grateau (2006) stated that the term 'medullar' referred to involvement of the bone marrow.
In a 33-year-old English man with lysozyme amyloidosis, Granel et al. (2006) identified the same T-to-A mutation. This patient had a dramatic bleeding episode due to rupture of abdominal lymph nodes.
Camara, V. M., Harding, J. W., Prieur, D. J. Inherited lysozyme deficiency in rabbits: the absence of a primary isozyme of lysozyme as the cause of the condition. Lab. Invest. 63: 544-550, 1990. [PubMed: 2232706]
Canet, D., Sunde, M., Last, A. M., Miranker, A., Spencer, A., Robinson, C. V., Dobson, C. M. Mechanistic studies of the folding of human lysozyme and the origin of amyloidogenic behavior in its disease-related variants. Biochemistry 38: 6419-6427, 1999. [PubMed: 10350460] [Full Text: https://doi.org/10.1021/bi983037t]
Dayhoff, M. O. Lactalbumin and Lysozyme. Atlas of Protein Sequence and Structure. Vol. 5. Washington: National Biomedical Research Foundation (pub.) 1972. Pp. D133-D140.
Dumoulin, M., Last, A. M., Desmyter, A., Decanniere, K., Canet, D., Larsson, G., Spencer, A., Archer, D. B., Sasse, J., Muyldermans, S., Wyns, L., Redfield, C., Matagne, A., Robinson, C. V., Dobson, C. M. A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme. Nature 424: 783-788, 2003. [PubMed: 12917687] [Full Text: https://doi.org/10.1038/nature01870]
Fleming, A., Allison, V. D. Observations on a bacteriolytic substance ('lysozyme') found in secretions and tissues. Brit. J. Exp. Path. 3: 252-260, 1922.
Fleming, A. On a remarkable bacteriolytic element found in tissues and secretions. Proc. Roy. Soc. Ser. B. 93: 306-317, 1922.
Gillmore, J. D., Booth, D. R., Madhoo, S., Pepys, M. B., Hawkins, P. N. Hereditary renal amyloidosis associated with variant lysozyme in a large English family. Nephrol. Dial. Transplant. 14: 2639-2644, 1999. [PubMed: 10534505] [Full Text: https://doi.org/10.1093/ndt/14.11.2639]
Granel, B., Serratrice, J., Disdier, P., Weiller, P.-J., Valleix, S., Grateau, G., Droz, D. Underdiagnosed amyloidosis: amyloidosis of lysozyme variant. (Letter) Am. J. Med. 118: 321-323, 2005. [PubMed: 15745733] [Full Text: https://doi.org/10.1016/j.amjmed.2004.10.022]
Granel, B., Serratrice, J., Valleix, S., Grateau, G., Droz, D., Lafon, J., Sault, M.-C., Chaudier, B., Disdier, P., Laugier, R., Delpech, M., Weiller, P.-J. A family with gastrointestinal amyloidosis associated with variant lysozyme. Gastroenterology 123: 1346-1349, 2002. [PubMed: 12360495] [Full Text: https://doi.org/10.1053/gast.2002.36022]
Granel, B., Valleix, S., Serratrice, J., Cherin, P., Texeira, A., Disdier, P., Weiller, P.-J., Grateau, G. Lysozyme amyloidosis: report of 4 cases and a review of the literature. Medicine 85: 66-73, 2006. [PubMed: 16523055] [Full Text: https://doi.org/10.1097/01.md.0000200467.51816.6d]
Grateau, G. Personal Communication. Paris, France 1/16/2006.
Greenwald, R. A., Cantor, J. O., Prieur, D. J., Young, D. M. Composition of cartilage from lysozyme-deficient rabbits. Biochim. Biophys. Acta 385: 435-437, 1975. [PubMed: 1125267] [Full Text: https://doi.org/10.1016/0304-4165(75)90375-x]
Harrison, R. F., Hawkins, P. N., Roche, W. R., MacMahon, R. F. T., Hubscher, S. G., Buckels, J. A. C. 'Fragile' liver and massive hepatic haemorrhage due to hereditary amyloidosis. Gut 38: 151-152, 1996. [PubMed: 8566845] [Full Text: https://doi.org/10.1136/gut.38.1.151]
Lanham, J. G., Meltzer, M. L., de Beer, F. C., Hughes, G. R. V., Pepys, M. B. Familial amyloidosis of Ostertag. Quart. J. Med. 51: 25-32, 1982. [PubMed: 7111672]
Neufeld, E. L. Personal Communication. Bethesda, Maryland 1972.
Pepys, M. B., Hawkins, P. N., Booth, D. R., Vigushin, D. M., Tennent, G. A., Soutar, A. K., Totty, N., Nguyen, O., Blake, C. C. F., Terry, C. J., Feest, T. G., Zalin, A. M., Hsuan, J. J. Human lysozyme gene mutations cause hereditary systemic amyloidosis. Nature 362: 553-557, 1993. [PubMed: 8464497] [Full Text: https://doi.org/10.1038/362553a0]
Peters, C. W. B., Kruse, U., Pollwein, R., Grzeschik, K.-H., Sippel, A. E. The human lysozyme gene: sequence organization and chromosomal localization. (Abstract) Cytogenet. Cell Genet. 51: 1059 only, 1989.
Prieur, D. J., Olson, H. M., Young, D. M. Lysozyme deficiency--an inherited disorder of rabbits. Am. J. Path. 77: 283-296, 1974. [PubMed: 4447131]
Prieur, D. J. Personal Communication. Pullman, Washington 5/13/1975.
Stumpf, A. M. Personal Communication. Baltimore, Md. 1/17/2025.
Taniyama, Y., Kuroki, R., Omura, F., Seko, C., Kikuchi, M. Evidence for intramolecular disulfide bond shuffling in the folding of mutant human lysozyme. J. Biol. Chem. 266: 6456-6461, 1991. [PubMed: 2007594]
Valleix, S., Drunat, S., Philit, J.-B., Adoue, D., Piette, J.-C., Droz, D., MacGregor, B., Canet, D., Delpech, M., Grateau, G. Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family. Kidney Int. 61: 907-912, 2002. [PubMed: 11849445] [Full Text: https://doi.org/10.1046/j.1523-1755.2002.00205.x]
Yazaki, M., Farrell, S. A., Benson, M. D. A novel lysozyme mutation phe57ile associated with hereditary renal amyloidosis. Kidney Int. 63: 1652-1657, 2003. [PubMed: 12675840] [Full Text: https://doi.org/10.1046/j.1523-1755.2003.00904.x]
Yoshimura, K., Toibana, A., Nakahama, K. Human lysozyme: sequencing of a cDNA, and expression and secretion by Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 150: 794-801, 1988. [PubMed: 2829884] [Full Text: https://doi.org/10.1016/0006-291x(88)90461-5]
Zalin, A. M., Jones, S., Fitch, N. J. S., Ramsden, D. B. Familial nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry and chemistry. Quart. J. Med. 81: 945-956, 1991. [PubMed: 1808634]