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Abstract: PO1335

Primary AA Amyloidosis due to a chr11:18287683 T>C (hg19) Mutation in the SAA1 Promoter Linked to the Amyloidogenic SAA1.1 Haplotype

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Sikora, Jakub, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Musalkova, Dita, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Prikryl, Petr, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Hartmannova, Hana, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Hodanova, Katerina, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Treslova, Helena, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Noskova, Lenka, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Stranecky, Viktor, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Jirsa, Milan, Institut klinicke a experimentalni mediciny Pracoviste laboratornich metod, Praha, Czechia
  • Zivna, Martina, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
  • Rychlík, Ivan, Univerzita Karlova 3 lekarska fakulta, Praha, Praha, Czechia
  • Rysava, Romana, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
  • Kmoch, Stanislav, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
Background

AA amyloidosis results from deposition of amyloid A (AA), a product of the proteolytic cleavage of serum amyloid A (SAA) proteins. Previously described AA amyloidosis has been due to increased production and deposition of serum amyloid A (SAA) proteins secondary to inflammatory conditions arising from infectious or metabolic causes. We describe for the first time a family with primary AA amyloidosis due to an isolated increase in production of AA protein.

Methods

A family was identified with autosomal dominant transmission of amyloidosis affecting 12 family members and associated with progressive chronic kidney disease (CKD) as well as other systemic manifestations of amyloidosis. Family members underwent measurement of serum SAA1 and whole exome sequencing with targeted sequencing. The luciferase reporter assay was used to determine promoter activity.

Results

Affected individuals developed proteinuria, CKD and systemic deposition of amyloid composed specifically of the SAA1.1 isoform. Affected individuals had a doubling of the SAA1 promoter activity and sustained elevation of serum SAA levels that segregated in an autosomal dominant pattern in 12 genetically affected and in none of 6 genetically unaffected relatives with a LOD score of >5. Genetic evaluation revealed a chr11:18287683 T>C (hg19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype that segregated completely with affected individuals. Tocilizumab had a beneficial effect when prescribed early.

Conclusion

A mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype led to a doubling of production of SAA1, leading to characteristic findings of amyloidosis. This is the first investigation to show that all manifestations of AA amyloidosis in humans are due solely to SAA overexpression. Idiopathic forms represent a significant and increasing proportion (15-20%) of all diagnosed cases of AA amyloidosis. Genetic screening of the SAA1 promoter should be pursued in individuals with AA amyloidosis without an obvious cause of systemic inflammation, especially if there is a positive family history. Contact ableyer@wakehealth.edu for genetic evaluation of familial amyloidosis.