title: ALys amyloidosis caused by compound heterozygosity in exon 2 (Thr70Asn) and exon 4 (Trp112Arg) of the lysozyme gene.
abstract: Hereditary amyloidoses are caused by germline mutations, which increase the propensity of a protein to form cross-beta aggregates and deposit as amyloid. Hereditary amyloidoses are particularly interesting as they help to understand how changes in the primary structure of an otherwise non-amyloidogenic protein contribute to amyloidogenesis. Here we report on a novel form of systemic ALys amyloidosis, caused by compound heterozygosity in exon 2 (p.T70N) and exon 4 (p.W112R) of the lysozyme gene (LYZ), with both mutations being present on the same allele. This type of hereditary ALys amyloidosis is characterized by extended amyloid deposits in the upper gastrointestinal tract, entire colon, and kidney, leading to gastrointestinal bleeding. Both mutations are probably effective in disease manifestation. The novel mutation at position 112 in the mature protein is located within the alpha-helical domain of the protein and therefore outside the cluster of residues that has so far been implicated in ALys amyloidosis. Taken together with the p.T70N mutation, this results in a lysozyme species where the correct folding of various protein domains is probably impaired and increases the propensity of amyloid fibril formation. Interestingly, this form of ALys amyloidosis is also characterized by the occurrence of proteolytic fragments of lysozyme in the amyloid deposits.
authors.affiliation: Institute of Pathology, Otto-von-Guericke-University, Magdeburg, Germany. christoph.roecken@medizin.uni-magdeburg.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.forename: Konrad
authors.initials: K
authors.lastname: Becker
authors.forename: Marcus
authors.initials: M
authors.lastname: Fändrich
authors.forename: Volker
authors.initials: V
authors.lastname: Schroeckh
authors.forename: Barbara
authors.initials: B
authors.lastname: Stix
authors.forename: Thomas
authors.initials: T
authors.lastname: Rath
authors.forename: Thilo
authors.initials: T
authors.lastname: Kähne
authors.forename: Jutta
authors.initials: J
authors.lastname: Dierkes
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.forename: Franz Werner
authors.initials: FW
authors.lastname: Albert
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism; D000686:Amyloidosis / Q000201:enzymology* / Q000235:genetics*; D015153:Blotting, Western; D003106:Colon / Q000473:pathology; D004252:DNA Mutational Analysis; D004386:Duodenum / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D009113:Muramidase / Q000737:chemistry / Q000235:genetics*; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D009113:Muramidase