A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis

Jakub Sikora, Tereza Kmochová, Dita Mušálková, Michal Pohludka, Petr Přikryl, Hana Hartmannová, Kateřina Hodaňová, Helena Trešlová, Lenka Nosková, Lenka Mrázová, Viktor Stránecký, Mariia Lunová, Milan Jirsa, Eva Honsová, Surendra Dasari, Ellen D. McPhail, Nelson Leung, Martina Živná, Anthony J. Bleyer, Ivan RychlíkRomana Ryšavá, Stanislav Kmoch

Research output: Contribution to journalArticlepeer-review


Amyloid A amyloidosis is a serious clinical condition resulting from the systemic deposition of amyloid A originating from serum amyloid A proteins with the kidneys being the most commonly and earliest affected organ. Previously described amyloid A amyloidosis is linked to increased production and deposition of serum amyloid A proteins secondary to inflammatory conditions arising from infectious, metabolic, or genetic causes. Here we describe a family with primary amyloid A amyloidosis due to a chr11:18287683 T>C (human genome version19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype. This condition leads to a doubling of the basal SAA1 promoter activity and sustained elevation of serum amyloid A levels that segregated in an autosomal dominant pattern in 12 genetically affected and in none of six genetically unaffected relatives, yielding a statistically significant logarithm of odds (LOD) score over 5. Affected individuals developed proteinuria, chronic kidney disease and systemic deposition of amyloid composed specifically of the SAA1.1 isoform. Tocilizumab (a monoclonal antibody against the interleukin-6 receptor) had a beneficial effect when prescribed early in the disease course. Idiopathic forms represent a significant and increasing proportion (15-20%) of all diagnosed cases of amyloid A amyloidosis. Thus, genetic screening of the SAA1 promoter should be pursued in individuals with amyloid A amyloidosis and no systemic inflammation, especially if there is a positive family history.

Original languageEnglish (US)
Pages (from-to)349-359
Number of pages11
JournalKidney international
Issue number2
StatePublished - Feb 2022


  • AA amyloidosis
  • chronic kidney disease
  • promoter mutation
  • serum amyloid A
  • tocilizumab
  • whole-genome sequencing

ASJC Scopus subject areas

  • Nephrology


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