In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations.
While the spectrum of APOA1 mutations provides no particular mechanistic insights, molecular diagnosis may still be important due to clinical differences between amyloidosis resulting from mutation in APOA1 vs. other genes.
The clinical spectrum and outcome of hereditary apolipoprotein A-Iamyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease.
The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis.
Mutations in human apolipoprotein A-I (apoA-I) are associated with low high-density lipoprotein (HDL) cholesterol levels and pathological conditions such as premature atherosclerosis and amyloidosis.
ApoA-I variants with amino acid substitutions, especially in the region of amino acid residues 50-93 and 170-178, have been 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.
The aim of this study was to evaluate the extent of amyloid deposits in explanted livers from two patients with apolipoprotein A-Iamyloidosis, with the Arg26 mutation, to determine their suitability as domino donors.
These data suggest that deletion of apoA-I is associated with increased clearance of Aβ and reduced parenchymal and vascular Aβ pathology in the Tg2576 model.
Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis.
A new genetic variant of hereditary apolipoprotein A-Iamyloidosis: a case-report followed by discussion of diagnostic challenges and therapeutic options.
The decreased affinity of ApoA-I amyloidogenic variants for lipids, together with the increased efficiency in the cholesterol efflux process, could explain why, despite the unfavourable lipid profile, patients affected by ApoA-I related amyloidosis do not show a higher CVD risk.
In ApoA-I related amyloidosis involving the heart, amyloid deposits are mainly constituted by the 93-residue N-terminal region of the protein, here indicated as [1-93]ApoA-I.
Both of them were able to avoid the aggregation of Aβ in vitro, even though recombinant ApoA-I-M was significantly more effective in protecting endothelial cells from Aβ(1-42)-toxicity.
The new insights in the understanding of the association of apoA-I with HDL, its metabolism, and its hypothesized structural findings may explain a common mechanism for the genesis of apoA-I induced amyloidosis.