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ALys amyloidosis caused by compound heterozygosity in Exon 2 (Thr70Asn) and Exon 4 (Trp112Arg) of the lysozyme gene
Author(s) -
Röcken Christoph,
Becker Konrad,
Fändrich Marcus,
Schroeckh Volker,
Stix Barbara,
Rath Thomas,
Kähne Thilo,
Dierkes Jutta,
Roessner Albert,
Albert Franz Werner
Publication year - 2006
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9393
Subject(s) - exon , amyloidosis , lysozyme , biology , point mutation , amyloid (mycology) , loss of heterozygosity , gene , mutation , microbiology and biotechnology , compound heterozygosity , genetics , allele , pathology , medicine , botany
Hereditary amyloidoses are caused by germline mutations, which increase the propensity of a protein to form cross‐β 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 α‐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. © 2005 Wiley‐Liss, Inc.