Aline Morgan Alvarenga1, Nathália Kozikas da Silva2, Paula Fernanda Silva Fonseca3, Theo G M Oliveira4, Jacilene Barbosa da Silva Monteiro5, Rodolfo Delfini Cançado6, Flavio Augusto Naoum7, Carla Luana Dinardo8, Pierre Brissot9, Paulo Caleb Junior Lima Santos10. 1. Department of Pharmacology - Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-Unifesp), São Paulo, Brazil. Electronic address: a.cmorgan@hotmail.com. 2. Department of Pharmacology - Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-Unifesp), São Paulo, Brazil. Electronic address: nathalia.kozikas@unifesp.br. 3. Department of Pharmacology - Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-Unifesp), São Paulo, Brazil. Electronic address: paulafonseca@usp.br. 4. Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil. Electronic address: theo.gremen@usp.br. 5. Department of Pharmacology - Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-Unifesp), São Paulo, Brazil. Electronic address: jacybiologa@hotmail.com. 6. Hematology Division, Santa Casa de São Paulo Medical School, Brazil. Electronic address: rdcan@uol.com.br. 7. Academia de Ciência e Tecnologia, São José do Rio Preto, Brazil. Electronic address: fnaoum@hotmail.com. 8. Fundação Pró-Sangue, Hemocentro de São Paulo, São Paulo, SP, Brazil; Universidade de São Paulo (USP), São Paulo, SP, Brazil. Electronic address: caludinardo@gmail.com. 9. Institut NuMeCan, Inserm U-1241, Univ Rennes 1, Rennes, France. Electronic address: pierre.brissot@gmail.com. 10. Department of Pharmacology - Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-Unifesp), São Paulo, Brazil. Electronic address: paulo.caleb@unifesp.br.
Abstract
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.
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 HFEp.Cys282Tyr mutation. MATERIALS AND METHODS: Fifty-three patients with primary IO and non-homozygous genotype for the HFEp.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.