HEREDITARY NEPHROPATHIC SYSTEMIC AMYLOIDOSIS CAUSED BY A NOVEL VARIANT APOLIPOPROTEIN-A-I

We report a family with autosomal-dominant hereditary systemic amyloid osis in three generations, presenting with renal involvement. Two memb ers of the current generation received renal transplants for end-stage renal failure 16 and 18 years ago, and remain ver, well clinically de spite massive visceral amyloidosis. Two other members of this generati on, aged 32 and 47 years, have massive systemic amyloid but no clinica l disability. Individuals known to be affected in previous generations died of renal failure in early adult life. Amyloid deposits in the pr oband, one of the transplanted individuals, were composed of apolipopr otein A-I (apoA-I), and among living family members there was complete concordance between amyloidosis and the presence of a novel 9 base pa ir in-frame deletion mutation in exon 4 of the apoA-I gene, causing a loss of residues Glu70Phe71Trp72. This predicts the acquisition of a s ingle extra positive charge by mature apoA-I, and this variant was det ected in the plasma of all carriers. All the previously reported amylo idogenic variants of apoA-I also carry an extra positive charge, indic ating that this electrostatic change is likely to be relevant to the a myloidogenicity of apoA-I.