Fibrinogen A alpha chain mutation (Arg554 Leu) associated with hereditary renal amyloidosis in a French family.

A French family with hereditary renal amyloidosis (HRA) was studied. The disease presented in 7 of the 8 affected individuals with proteinuria or the nephrotic syndrome. The age of onset was in the fifth decade of life. There is currently no sign of extrarenal involvement in any affected individual. However, the nephropathy in this family is progressive and led to terminal renal failure in 4 patients. Immunohistochemistry studies of glomerular amyloid deposits suggested that the amyloid protein was the fibrinogen A alpha chain. Direct DNA sequencing revealed a G 4993 T transversion and subsequently Arg 554 Leu mutation in the fibrinogen A alpha chain. This is the first description of this fibrinogen A alpha chain mutation in Europe. This family is of French descent and cannot be related to the previously reported Peruvian/Mexican and African-American kindreds.

Hereditary amyloid cardiomyopathy caused by a variant apolipoprotein A1.

Autosomal dominant hereditary amyloidosis with a unique cutaneous and cardiac presentation and death from heart failure by the sixth or seventh decade was found to be associated with a previously unreported point mutation (thymine to cytosine, nt 1389) in exon 4 of the apolipoprotein A1 (apoA1) gene. The predicted substitution of proline for leucine at amino acid position 90 was confirmed by structural analysis of amyloid protein isolated from cardiac deposits of amyloid. The subunit protein is composed exclusively of NH2-terminal fragments of the variant apoA1 with the longest ending at residue 94 in the wild-type sequence. Amyloid fibrils derived from four previously described apoA1 variants are composed of similar fragments with carboxyl-terminal heterogeneity, but contrary to those variants, which all carry one extra positive charge, the substitution Leu90Pro does not result in any charge modification. It is unlikely, therefore, that amyloid fibril formation is related to change of charge for a specific residue of the precursor protein. This is in agreement with studies on transthyretin amyloidosis in which no unifying factor such as change of charge for amino acid residues has been noted.

Renal amyloidosis with a frame shift mutation in fibrinogen aalpha-chain gene producing a novel amyloid protein.

A French kindred with autosomal dominant hereditary renal amyloidosis was found to have a novel mutation in the fibrinogen Aalpha-chain gene. In this kindred, renal disease appeared early in life and led to terminal renal failure at an early age. Renal transplantation resulted in rapid destruction of the allograft by amyloid deposition within 2 years. Amyloid fibril protein isolated from a transplanted kidney was found to contain a novel, hybrid peptide of 49 residues whose N-terminal 23 amino acids were identical to residues 499 to 521 of normal fibrinogen Aalpha-chain. The remainder of the peptide (26 residues) represented a completely new sequence for mammalian proteins. DNA sequencing documented that the new sequence was the result of a single nucleotide deletion at position 4897 of the fibrinogen Aalpha-chain gene that gives a frame-shift at codon 522 and premature termination at codon 548. The contributions toward fibrillogenesis of the two portions of the amyloid fibril protein, ie, N-terminal fibrinogen sequence and C-terminal novel sequence, are presently unknown. However, the early onset and rapid reoccurrence of amyloid in renal transplants is unlike the clinical course with other amyloid proteins having single amino acid substitutions that give hereditary renal amyloidosis. Liver transplantation to stop synthesis of this abnormal hepatic derived protein should be considered early in the course of the disease.