A missense mutation in the SAA1 protein causing hereditary amyloid A amyloidosis

Abstract

In summary, guided by the patient's clinical course and diagnostic challenges, we report, for the first time, a family with autosomal dominant hereditary AA amyloidosis caused by a heterozygous SAA1 missense mutation, p.D34V. This mutation alters the primary structure of SAA1, dominantly enhances its aggregation, and produces a highly amyloidogenic protein capable of forming amyloid even at normal plasma SAA levels, affecting patients in their 20s and 30s. Importantly, the mutant protein escapes detection by routine clinical MS/MS amyloid typing because of its location between 2 trypsin cleavage sites. These findings highlight the need for genetic testing in AA amyloidosis without an inflammatory cause and caution that segmental duplications within SAA genes may complicate variant calling from short-read sequencing, further challenging diagnosis. Because of the unique pathogenesis of this family, the traditional immunosuppressive therapy used in AA amyloidosis would have no effect because the SAA levels were already low or normal. A novel approach to AA amyloidosis therapy would be required to treat members of this family and others like them.