Identification of new BMP6 pro-peptide mutations in patients with iron overload.
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 late-onset 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.
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy; Veneto Region Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Chiara
C
Piubelli
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy; Veneto Region Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Annalisa
A
Castagna
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy; Veneto Region Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Giacomo
G
Marchi
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy; Veneto Region Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Monica
M
Rizzi
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy; Veneto Region Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Fabiana
F
Busti
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy; Veneto Region Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Sadaf
S
Badar
Hematology section, Oncology Unit, Azienda Sanitaria Locale, Ospedale "Cardinal Massaia", Asti, Italy.
Monia
M
Marchetti
Department of Clinical and Biological Sciences, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Turin, Italy.
Marco
M
De Gobbi
Department of Clinical and Biological Sciences, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Turin, Italy.
Antonella
A
Roetto
Department of Biotechnology, University of Verona, Verona, Italy.
Luciano
L
Xumerle
Department of Biotechnology, University of Verona, Verona, Italy.
Eda
E
Suku
Department of Biotechnology, University of Verona, Verona, Italy.
Alejandro
A
Giorgetti
Department of Biotechnology, University of Verona, Verona, Italy.
Massimo
M
Delledonne
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy; Veneto Region Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Oliviero
O
Olivieri
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy; Veneto Region Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Domenico
http://orcid.org/0000-0001-9684-1899
D
Girelli
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D015415:Biomarkers; D055418:Bone Morphogenetic Protein 6 / Q000737:chemistry / Q000235:genetics*; D003062:Codon; D005260:Female; D020022:Genetic Predisposition to Disease; D006432:Hemochromatosis / Q000150:complications / Q000235:genetics; D064451:Hepcidins / Q000097:blood / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D019190:Iron Overload / Q000175:diagnosis / Q000209:etiology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*
D015415:Biomarkers; D055418:Bone Morphogenetic Protein 6; D003062:Codon; D064451:Hepcidins