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

First author: Nelson Leung

Journal: Kidney International (2026), 110:255–259

PubMed link: https://pubmed.ncbi.nlm.nih.gov/41887599/

Summary by Prof. Sophie Georgin-Lavialle and Dr Rim Bourguiba

Key points

• Description of a familial form of AA amyloidosis due to a heterozygous SAA1 mutation.

• The presentation is unusual because there is no inflammatory syndrome and circulating SAA levels are normal or low.

• The p.D34V mutation markedly increases SAA1’s ability to form amyloid fibrils.

• This abnormality may not be detected by standard proteomic typing.

• A genetic cause should be considered in familial AA amyloidosis or AA amyloidosis without an obvious inflammatory cause.

Summary

This article reports a family affected by hereditary AA amyloidosis linked to an SAA1 mutation. The index case is a 37-year-old man investigated for significant proteinuria; kidney biopsy showed AA amyloid deposits. However, the presentation did not match “classic” AA amyloidosis: there was no inflammatory syndrome, no CRP elevation, and circulating SAA was below the detection threshold. The family history was highly suggestive, with several relatives affected by renal or systemic amyloidosis and early deaths, pointing toward autosomal dominant inheritance.

Whole-exome sequencing identified in affected individuals a heterozygous missense variant in SAA1, c.101A>T, leading to the p.D34V substitution. This variant was absent in the unaffected father and not present in population databases. Prior genetic investigations for an autoinflammatory disease were negative. The authors emphasize that this variant lies in a genomic region that can be masked in some standard analyses, creating a risk of missed diagnosis.

The work is also methodologically noteworthy. With conventional mass spectrometry, deposits were typed as AA amyloidosis with predominance of SAA1, but without detection of the mutant protein. In fact, the D34V substitution lies between two tryptic cleavage sites, making the mutant peptide difficult to detect with standard workflows. Using an alternative digestion with Asp-N enabled identification of the mutant peptide in amyloid deposits. Importantly, deposits preferentially contained the mutant form of SAA1, suggesting it aggregates much more readily than the wild-type protein.

Structural and functional analyses were consistent with this. The mutation replaces a negatively charged aspartic acid with a hydrophobic valine in a region important for fibrillogenesis. This change destabilizes the native structure of SAA1 and promotes its conversion into amyloid fibrils. Experiments with synthetic peptides showed a clear increase in aggregation of the mutant peptide, with higher Thioflavin T signal and abundant fibrils on electron microscopy, whereas the wild-type peptide aggregated little under the same conditions.

Overall, this work describes a new cause of hereditary AA amyloidosis, independent of chronic inflammation and driven by the intrinsic amyloidogenicity of mutant SAA1. Clinically, the message is important: in AA amyloidosis without an obvious inflammatory cause - especially in younger patients and/or in the presence of a family history - a genetic etiology should be considered and the SAA1 gene carefully analyzed. This observation also raises management questions, as usual AA amyloidosis treatments aimed at reducing SAA production (e.g., anti–IL-6 therapies) may have limited efficacy in this context.