A novel Y231del mutation of HFE in hereditary haemochromatosis provides in vivo evidence that the Huh‐7 is a human haemochromatotic cell line

Abstract

Hereditary haemochromatosis (HH), which is mainly associated with a C282Y polymorphism in HFE, is common among Caucasians of north European descent, but is very rare among Asians. Herein, we report a 43-year-old Japanese man who was diagnosed as having HH. A laboratory examination revealed an elevated serum iron level (280 μg/dl), hyperferritinemia (1698 ng/ml) and a low serum level of hepcidin-25 (4.0 ng/ml). Abdominal magnetic resonance imaging revealed findings suggestive of iron accumulation in the liver and pancreas. HFE gene sequencing in the patient revealed a novel homozygous TAC nucleotide deletion (c. 691_693del) responsible for the loss of a tyrosine at position 231 (p. Y231del) of the HFE protein. This homozygous Y231del mutation was recently found in the Huh-7 hepatoma cell line and was shown to prevent the translocation of HFE to the cell surface. This clinical case provides in vivo evidence suggesting that Huh-7 is undoubtedly a human haemochromatotic cell line and, as such, is a valuable tool for investigating the pathogenesis of HFE-related HH in humans.

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

“…41 In addition, researchers discovered a deletion (p.Y231del) in an Huh7 hepatoma cell line derived from a Japanese HH patient 46 which prevents HFE cell surface expression. The identical mutation has more recently been discovered in another Japanese patient, 47 showing, for the first time, that HFE -associated HH can also occur in Asians. Furthermore, a few Sardinian individuals show deletions of the entire HFE gene.…”

Iron storage disease in Asia‐Pacific populations: The importance of non‐HFE mutations

“…[18][19][20] Recently, a homozygous 3 nucleotide deletion causing a single amino acid deletion (Y231del) was identified in a Japanese patient with HH. 21 Interestingly, this mutation had been previously identified in a commonly used human hepatoma cell line (Huh-7) that had been originally derived from a Japanese hepatoma patient, proving that this cell line is in fact hemochromatotic in origin. 22 Finally, a homozygous splice site mutation, IVS5+1 G>A, was reported in a Vietnamese family with HH.…”

“…The E277K mutation in HFE , which has a functional effect on the protein, has been reported in Asian individuals and has also been associated with a HH phenotype in Portugal . Recently, a homozygous 3 nucleotide deletion causing a single amino acid deletion (Y231del) was identified in a Japanese patient with HH . Interestingly, this mutation had been previously identified in a commonly used human hepatoma cell line (Huh‐7) that had been originally derived from a Japanese hepatoma patient, proving that this cell line is in fact hemochromatotic in origin .…”

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

“…The same mutation was found in the Huh-7 hepatoma cell line and was shown to prevent the translocation of HFE to the cell surface [88]. In addition, families with various types of HH were sporadically reported from Asian countries, including Japan, China, and Pakistan [67,87,[89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104]. In Japan, mutations in HFE2 (type 2A), TFR2 (type 3), and SLC40A1 (type 4) seem relatively common causes of HH [97].…”

“…In the literature, I could find only one Japanese hemochromatosis case harboring the homozygous HFE C282Y mutation [86]. However, a Japanese family with a homozygous mutation of HFE (c. 691_693del) responsible for the loss of a tyrosine at the position 231 (p. Y231del) of the HFE protein has been reported [87]. The same mutation was found in the Huh-7 hepatoma cell line and was shown to prevent the translocation of HFE to the cell surface [88].…”