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Human lysozyme gene mutations cause hereditary systemic amyloidosis
M B Pepys1, P N Hawkins, D R Booth
1Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Nature
|April 8, 1993
Summary
Hereditary systemic amyloidosis, typically fatal by age 50, can be caused by mutations in the lysozyme gene. This study identifies lysozyme as the amyloid fibril protein in two families, revealing new insights into disease mechanisms.
Area of Science:
- Genetics
- Biochemistry
- Medicine
Background:
- Hereditary non-neuropathic systemic amyloidosis (Ostertag-type) is a rare, autosomal dominant disorder.
- Amyloid deposition in visceral organs often leads to fatality by the fifth decade.
- While some cases are linked to apolipoprotein AI gene mutations, this study investigates alternative genetic causes.
Purpose of the Study:
- To identify the amyloid fibril protein in two English families with hereditary systemic amyloidosis.
- To investigate the genetic basis of amyloidogenesis in these families.
- To characterize novel mutations in the lysozyme gene associated with this disease.
Main Methods:
- Protein analysis of amyloid deposits to identify the fibril protein.
- Genetic sequencing of the apolipoprotein AI and lysozyme genes in affected individuals.
- Biochemical characterization of the identified lysozyme variants.
Main Results:
- Lysozyme, not apolipoprotein AI, was identified as the amyloid fibril protein in the studied families.
- Two distinct point mutations in the lysozyme gene were discovered, leading to amino acid substitutions (Ile56Thr and Asp67His).
- Amyloid fibrils were composed of the full-length Thr-56 variant lysozyme.
Conclusions:
- This is the first report of naturally occurring human lysozyme variants causing disease.
- Lysozyme gene mutations are a newly identified cause of hereditary systemic amyloidosis.
- The findings provide a valuable model for understanding amyloidogenesis due to the known structure of lysozyme.