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

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.

Hemochromatosis classification: update and recommendations by the BIOIRON Society

“… Others do not display variants in any of the 5 classical hemochromatosis genes (ie, HFE, HAMP , HJV , TFR2 , and SLC40A1 ). Recently, some small case series 96 , 97 , 98 have reported moderate late-onset IO in patients carrying variants in the BMP6 gene, encoding one of the major activators of hepcidin expression in response to iron. 99 The role of such variants is still controversial, as they have been detected mostly in patients with a substantial burden of acquired cofactors.…”

Iron-dependent BMP6 Regulation in Liver Sinusoidal Endothelial Cells Is Instructed by Hepatocyte-derived Secretory Signals

“…However, lack of BMP6 does not affect bone homeostasis, but causes systemic iron overload in mice. 3 Moreover, BMP6 mutations are associated with iron overload in patients, [4][5][6][7][8] supporting its crucial regulatory function in iron metabolism. In the liver, BMP6 is mainly produced by liver sinusoidal endothelial cells (LSECs).…”

Brazilian family with hyperferritinemia-cataract syndrome: case report

“…After sequencing, the electropherogram was analyzed using the Geneious software (Biomatters). (15) Sequencing of the 5'UTR region of the FTL gene revealed the pathogenic c.-164C>G mutation (Figure 1), first described in 2006, in all three family members. (16) The Ethics Committee of Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo approved the study protocol (CAAE: 01507518.5.0000.5505; # 3.439.573).…”