Hereditary apolipoprotein AI-associated amyloidosis in surgical pathology specimens: identification of three novel mutations in the APOA1 gene

Abstract

Apolipoprotein AI-derived (AApoAI) amyloidosis may present either as a non-hereditary form with wild-type protein deposits in atherosclerotic plaques or as a hereditary form due to germline mutations in the APOA1 gene. Currently, more than 50 apoAI variants are known, and 13 are associated with amyloidosis. We describe six patients with AApoAI amyloidosis due to APOA1 germline mutations that affect the larynx, small intestine, large intestine, heart, liver, kidney, uterus, ovary, or pelvic lymph nodes. In each patient, the amyloid showed a characteristic apple green birefringence when viewed under polarized light after Congo red staining and was immunoreactive with antibodies against apoAI. Sequence analyses revealed one known (p.Leu75Pro) and three novel APOA1 mutations that included gene variations leading to two different frameshifts (p.Asn74fs and p.Ala154fs) and one amino acid exchange (p.Leu170Pro). These three novel mutations extend our knowledge about both the location of the mutations and the organ distribution in hereditary AApoAI amyloidosis. Thirteen of the now sixteen amyloidogenic mutations are localized in two hot-spot regions that span residues 50 to 93 and 170 to 178. The organ distribution and clinical presentation of AApoAI amyloidosis seems to depend on the position of the mutation. Patients with alterations in codons 1 to 75 mostly develop hepatic and renal amyloidosis, while carriers of mutations in residues 173 to 178 mainly suffer from cardiac, laryngeal, and cutaneous amyloidosis.

Figure 1

Biopsies from the six patients with AApoAI amyloidosis.Histological examination of the biopsy and resection specimens revealed homogeneous eosinophilic deposits in H&E-stained sections (left panel). Same areas produced a typical apple green birefringence in polarized light after Congo red (CR) staining (center). Staining with an anti-apoAI antibody (right panel) showed a strong and even immunoreactivity of these amyloid deposits in every patient specimen. Sections from the patients 1–4 and 6 were stained with the alkaline phosphatase system (red color), whereas the section from patient No. 5 was stained with a DAB substrate kit (brown color). Scale bar=100 μm.

Figure 2

Distribution of ApoAI mutations with regard to the proteins secondary structure. The hot spot regions spanning residues 50 to 93 and 170 to 178 are marked in yellow and the twisted blue areas represent the α-helices. The picture of the secondary structure of ApoAI was obtained from the database Jpred at the European Bioinformatics Institute and modified.