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Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I
M R Persey1, D R Booth, S E Booth
1Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, England, United Kingdom.
Insights
Hereditary systemic amyloidosis linked to apolipoprotein A-I gene mutations can present with varying severity. A novel mutation shows a strong correlation with the disease, highlighting the role of electrostatic changes in amyloid formation.
Area of Science:
- Genetics
- Nephrology
- Biochemistry
Background:
- Hereditary systemic amyloidosis is a rare genetic disorder characterized by amyloid protein deposition in various organs.
- Renal involvement is a common and often severe manifestation, leading to end-stage renal failure.
- Apolipoprotein A-I (apoA-I) is a known component of certain types of systemic amyloidosis.
Purpose of the Study:
- To investigate the genetic basis of autosomal-dominant hereditary systemic amyloidosis in a multi-generational family.
- To identify the specific mutation responsible for amyloid formation and its clinical manifestations.
- To explore the relationship between the identified mutation and the electrostatic properties of apoA-I.
Main Methods:
- Family-based genetic analysis including pedigree tracing and mutation screening.
- Characterization of amyloid deposits in affected individuals.
- Analysis of apolipoprotein A-I gene sequence and protein properties.
Main Results:
- A novel 9 base pair in-frame deletion mutation in exon 4 of the apoA-I gene was identified in affected family members.
- This mutation leads to the loss of residues Glu70Phe71Trp72, predicting an extra positive charge in mature apoA-I.
- Amyloid deposits in the proband were confirmed to be composed of apoA-I.
- Complete concordance was observed between the presence of the mutation and systemic amyloidosis in living family members.
Conclusions:
- The identified apoA-I gene mutation is causative of autosomal-dominant hereditary systemic amyloidosis in this family.
- The acquisition of an extra positive charge in apoA-I is strongly implicated in its amyloidogenicity.
- Clinical presentation and severity of amyloidosis can vary significantly, even within the same family.
Abstract:
We report a family with autosomal-dominant hereditary systemic amyloidosis in three generations, presenting with renal involvement. Two members of the current generation received renal transplants for end-stage renal failure 16 and 18 years ago, and remain very well clinically despite massive visceral amyloidosis. Two other members of this generation, aged 32 and 47 years, have massive systemic amyloid but no clinical disability. Individuals known to be affected in previous generations died of renal failure in early adult life. Amyloid deposits in the proband, one of the transplanted individuals, were composed of apolipoprotein A-I (apoA-I), and among living family members there was complete concordance between amyloidosis and the presence of a novel 9 base pair in-frame deletion mutation in exon 4 of the apoA-I gene, causing a loss of residues Glu70Phe71Trp72. This predicts the acquisition of a single extra positive charge by mature apoA-I, and this variant was detected in the plasma of all carriers. All the previously reported amyloidogenic variants of apoA-I also carry an extra positive charge, indicating that this electrostatic change is likely to be relevant to the amyloidogenicity of apoA-I.