Related Experiment Videos
Renal amyloidosis caused by a novel stop-codon mutation in the apolipoprotein A-II gene
M Yazaki1, J J Liepnieks, T Yamashita
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 975 West Walnut Street, 1B-503, Indianapolis, IN 46202, USA.
Background:
Although apolipoprotein A-II (apoA-II) associated amyloidosis has been described in the senescent accelerated mouse (SAM) model of aging, so far there has been no report of human apoA-II amyloidosis except for a recent report of renal amyloidosis resulting from a stop-codon to glycine mutation of apoA-II. The mechanisms of amyloid formation in human apoA-II amyloidosis are not clear.
Methods:
A 46-year-old Caucasian male with proteinuria noted at 42 years of age was studied. Renal biopsy revealed amyloid deposition in glomeruli. DNA analysis of genes known to be associated with hereditary renal amyloidosis revealed no abnormalities. To elucidate the type of his amyloidosis, apoA-II gene and plasma apoA-II were examined.
Results:
DNA analysis revealed heterozygosity for a G to C transversion at the second position of the stop-codon of apoA-II gene, suggesting a stop to serine substitution at codon 78. Western blot analysis and amino acid sequence analysis of the patient's plasma apoA-II showed both normal apoA-II and variant apoA-II with a 21-amino acid residue extension at the C-terminus.
Conclusions:
These results indicate that the patient's amyloid fibrils were derived from apoA-II and the amyloidogenesis is likely to be closely linked to the peptide extension at the C-terminus of variant apoA-II. The pathogenesis of human apoA-II amyloidosis is different from that of SAM.
Insights
Human apolipoprotein A-II (apoA-II) amyloidosis is rare. A novel variant apoA-II with a C-terminal extension caused amyloid deposition in a patient, differing from mouse models.
Area of Science:
- Nephrology
- Genetics
- Biochemistry
Background:
- Human apolipoprotein A-II (apoA-II) amyloidosis is uncommon, unlike in the senescent accelerated mouse (SAM) model.
- Previous reports of human apoA-II amyloidosis are limited, with one case linked to a specific gene mutation.
Observation:
- A 46-year-old male presented with proteinuria and glomerular amyloid deposition.
- Genetic analysis for hereditary renal amyloidosis was negative.
- Investigation focused on apoA-II gene and plasma apoA-II to identify the amyloid type.
Findings:
- A novel mutation in the apoA-II gene resulted in a stop-to-serine substitution, creating a variant apoA-II with a 21-amino acid C-terminal extension.
- Both normal and variant apoA-II were detected in the patient's plasma.
Implications:
- The C-terminal extension of the variant apoA-II is implicated in the pathogenesis of this patient's amyloidosis.
- The mechanism of human apoA-II amyloidogenesis appears distinct from that observed in the SAM model.