Novel mutations in the bone morphogenetic protein 6 gene in patients with iron overload and non-homozygous genotype for the HFE p.Cys282Tyr mutation

Aline Morgan Alvarenga (1) , Nathália Kozikas da Silva (1) , Paula Fernanda Silva Fonseca (1) , Theo G M Oliveira , Jacilene Barbosa da Silva Monteiro (1) , Rodolfo Delfini Cançado , Flavio Augusto Naoum , Carla Luana Dinardo (2) , Pierre Brissot (3) , Paulo Caleb Junior Lima Santos (1)

1 Universidade Federal de São Paulo
2 USP - Universidade de São Paulo = University of São Paulo
3 NuMeCan - Nutrition, Métabolismes et Cancer

Background - Five main genes are associated with hemochromatosis; however, current studies show that, in addition to these genes, others may be associated with primary iron overload (IO). One of these is the bone morphogenetic protein 6 (BMP6), which encodes a protein that modulates hepcidin synthesis and, consequently, iron homeostasis. Aim - To identify BMP6 gene pathogenic variants in patients with IO and non-homozygous genotype for the HFE p.Cys282Tyr mutation. Materials and methods - Fifty-three patients with primary IO and non-homozygous genotype for the HFE p.Cys282Tyr were selected. Subsequent bidirectional DNA sequencing of BMP6 exons was performed. Results - Two novel variants were found. One at homozygous state p.Gln158Ter (c.472C>T) was pathogenic, the other one at heterozygous state p.Val394Met (c.1180G>A) was of uncertain significance (VUS); the third variant at heterozygous state p.Arg257His (c.770G>A) has already been described and associated with IO. No BMP6 pathogenic variants that would explain iron overload phenotypes were detected in 94% of the studied patients. Conclusion - Identification of the BMP6 pathogenic variants in Brazilian patients with primary IO might contribute to the genetic understanding of this phenotype.

Mots clés: BMP6; Hemochromatosis; Iron overload; Non-homozygous genotype for the HFE p.Cys282Tyr; Sequencing

Domaines: Génétique

Aline Morgan Alvarenga, Nathália Kozikas da Silva, Paula Fernanda Silva Fonseca, Theo G M Oliveira, Jacilene Barbosa da Silva Monteiro, et al.. Novel mutations in the bone morphogenetic protein 6 gene in patients with iron overload and non-homozygous genotype for the HFE p.Cys282Tyr mutation. Blood Cells, Molecules and Diseases, 2020, 84, pp.102444. ⟨10.1016/j.bcmd.2020.102444⟩. ⟨hal-02864471⟩