A novel hepcidin mutation

Area of Science:

• * Molecular genetics and endocrinology.
• * Iron metabolism and homeostasis.

Background:

• * Hepcidin-25, a bioactive peptide hormone, regulates iron levels by inhibiting plasma iron transport via ferroportin.
• * Hepcidin-25 is synthesized in the liver from pro-hepcidin.
• * A patient presented with unexplained infertility and fatigue, prompting investigation into potential genetic causes.

Purpose of the Study:

• * To identify the genetic basis of a patient's symptoms of fatigue, infertility, and iron overload.
• * To characterize the identified mutation in the HAMP gene.
• * To assess the clinical impact of the mutation on iron metabolism and endocrine function.

Main Methods:

• * Genomic DNA was purified from whole blood.
• * Multiplex Ligation-dependent Probe Amplification (MLPA) was used to detect large genomic rearrangements in the HAMP gene.
• * Plasma hepcidin-25 levels were quantified using liquid chromatography/tandem mass spectrometry (LC-MS/MS).

Main Results:

• * A novel homozygous mutation (c.215delG, p.Cys72Serfs*?) in the HAMP gene was identified, causing a frameshift.
• * Bioactive hepcidin-25 was undetectable in plasma, correlating with massive iron overload (ferritin up to 8360 µg/L).
• * The patient exhibited anemia (Hb 7.0 mmol/L) and hypogonadotropic hypogonadism (testosterone 1.2 nmol/L); treatment with venesection and gonadotropins improved symptoms and laboratory values.

Conclusions:

• * A novel mutation in the HAMP gene was identified as the cause of massive iron overload, fatigue, and hypogonadotropic hypogonadism.
• * This finding highlights the critical role of hepcidin in iron regulation and its impact on reproductive health.
• * Therapeutic interventions targeting iron overload and hormonal deficiencies can effectively manage symptoms associated with hepcidin deficiency.