HEREDITARY HEPATIC AND SYSTEMIC AMYLOIDOSIS CAUSED BY A NEW DELETION INSERTION MUTATION IN THE APOLIPOPROTEIN AL GENE/

We report a Spanish family with autosomal-dominant non-neuropathic her editary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the ap olipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValT hr. Affected individuals are heterozygous for this mutation and have b oth normal apoAI and variant molecules bearing one extra positive char ge, as predicted from the DNA sequence, The amyloid fibrils are compos ed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-t ype sequence,Amyloid fibrils derived from the other three known amyloi dogenic apoAI variants are also composed of similar NH2-terminal fragm ents. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it map be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, th is is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the a poAI model for investigation of molecular mechanisms of amyloid fibril logenesis.