Identification of new BMP6 pro‐peptide mutations in patients with iron overload

Abstract

Hereditary Hemochromatosis (HH) is a genetically heterogeneous disorder caused by mutations in at least five different genes (HFE, HJV, TFR2, SLC40A1, HAMP) involved in the production or activity of the liver hormone hepcidin, a key regulator of systemic iron homeostasis. Nevertheless, patients with an HH-like phenotype that remains completely/partially unexplained despite extensive sequencing of known genes are not infrequently seen at referral centers, suggesting a role of still unknown genetic factors. A compelling candidate is Bone Morphogenetic Protein 6 (BMP6), which acts as a major activator of the BMP-SMAD signaling pathway, ultimately leading to the upregulation of hepcidin gene transcription. A recent seminal study by French authors has described three heterozygous missense mutations in BMP6 associated with mild to moderate lateonset iron overload (IO). Using an updated next-generation sequencing (NGS)-based genetic test in IO patients negative for the classical HFE p.Cys282Tyr mutation, we found three BMP6 heterozygous missense mutations in four patients from three different families. One mutation (p. Leu96Pro) has already been described and proven to be functional. The other two (p.Glu112Gln, p.Arg257His) were novel, and both were located in the pro-peptide domain known to be crucial for appropriate BMP6 processing and secretion. In silico modeling also showed results consistent with their pathogenetic role. The patients' clinical phenotypes were similar to that of other patients with BMP6-related IO recently described. Our results independently add further evidence to the role of BMP6 mutations as likely contributing factors to late-onset moderate IO unrelated to mutations in the established five HH genes.

Non-HFE mutations in haemochromatosis in China: combination of heterozygous mutations involving HJV signal peptide variants

“…Cellular and animal models have identified BMPs, particularly BMP6, as compelling candidates for the class HH-related genes, but until recently, evidence in humans was limited to the possible role of common SNPs in BMP2 and BMP4 as modifiers of classical HFE-related HH 45. Most recently, BMP6 mutations were identified in HH, such as BMP6 p.L96P, p.E112Q and p.R257H 8. In the present study, BMP4 p.R269Q was first identified in an HH case.…”

“…Mutations in other types of HH include HJV p.G320V and p.I222N in type IIA HH,4 HAMP p.C78T in type IIB HH,5 TFR2 p.L99V, p.A75V and p.V277L in type III HH6 and SLC40A1 p.V162del in type IV HH 7. Mutations in BMP/SMAD pathway gene BMP6 , which is ultimately leading to the downregulation of hepcidin gene transcription, such as BMP6 p.L96P, have also been reported recently 8. In addition, next generation sequencing has identified novel genetic variants involved in iron metabolism, such as HEPHL1 p.D136V and GNPAT p.D519G 9 10…”

Modern iron replacement therapy: clinical and pathophysiological insights

“…1). Hepcidin synthesis by hepatocytes is stimulated when body iron stores are replete, mainly through a paracrine release of Bone Morphogenetic Protein 6 (BMP6) [26,27]. Indeed, BMP6 is produced by liver sinusoidal cells [28] in response to increased transferrin saturation [22], and stimulates the BMP/Small Mother Against Decapentaplegic (SMAD) signaling pathway critically involved in transcriptional regulation of hepcidin [26].…”

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

“…The heterozygous mutation of SLC40A1 Q248H is frequently observed in African populations and is associated with mild microcytic anemia and the tendency to iron overload [79,80]. Recently, families of HH harboring mutations in the propeptide of the BMP6 gene have been reported [81,82]. According to these studies, serum hepcidin levels of patients with heterozygous mutations of this gene were markedly low or inappropriately low for the iron overload.…”