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The molecular basis of hereditary hemochromatosis (HH) is more complex than previously expected. More than 80% of hemochromatosis probands of Northern European descent are homozygous for the C282Y HFE gene mutation. However, five novel non-related- HFE HH forms have now been identified. The transferrin receptor( TFR2)-linked form is inherited in an autosomal recessive pattern and is considered to be an adult-onset syndrome. Until now, it has been associated with five mutations that have only been detected in Japanese and southern European patients. Here, we report the identification of a novel TFR2 nonsense mutation in two related French adolescents. We discuss the phenotype of this sibling pair from precedent biological and clinical findings as well as the expected role of TFR2 in iron homeostasis. Finally, we suggest that iron overload phenotypes associated with mutations in TFR2 may be intermediate between those related to mutations in HFE and those related to mutations in juvenile hemochromatosis genes. [ABSTRACT FROM AUTHOR]

Background: Venesection is the key therapy in haemochromatosis, but it remains controversial in hyperferritinaemia with moderate iron accumulation. There is substantial evidence that the results of HFE genotyping are routinely misinterpreted, while elevated serum ferritin has become more frequent in recent years in white adult populations following the increase of obesity and metabolic traits., Aims: To examine the reasons for prescribing venesection in 1,059 French patients during the period 2012-2015, determine the true prevalence of HFE-related haemochromatosis, and compare iron overload profiles between haemochromatosis and non-haemochromatosis patients., Results: Only 258 of the 488 patients referred for haemochromatosis had the p.[Cys282Tyr];[Cys282Tyr] disease causative genotype (adjusted prevalence: 24.4%). Of the 801 remaining patients, 112 (14.0%) had the debated p.[Cys282Tyr];[His63Asp] compound heterozygote genotype, 643 (80.3%) had central obesity, 475 (59.3%) had metabolic syndrome (MetS) and 93 (11.6%) were heavy drinkers. The non-haemochromatosis patients started therapeutic venesection 9 years later than haemochromatosis patients (P < 0.001). Despite similar serum ferritin values, they had lower transferrin saturation (41.1% vs 74.3%; P < 0.001), lower amounts of iron removed by venesection (1.7 vs 3.2 g; P < 0.001) and lower hepatic iron concentrations (107 vs 237 µmol/g; P < 0.001)., Conclusions: Haemochromatosis is over-diagnosed and is no longer the main reason for therapeutic venesection in France. Obesity and other metabolic abnormalities are frequently associated with mild elevation of serum ferritin, the MetS is confirmed in ~50% of treated patients. There is a minimal relationship between serum ferritin and iron overload in non-p.Cys282Tyr homozygotes. Our observations raise questions about venesection indications in non-haemochromatosis patients., (© 2022 John Wiley & Sons Ltd.)

Ferroportin-related iron overload disease differs from haemochromatosis in that it has a dominant mode of inheritance and is usually associated with macrophage iron sequestration. However, it is thought that mutations with opposite effects on protein functions, i.e. loss-of-function versus gain-of-function mutations, are responsible for variable phenotype presentations. The present study investigated the functional relevance of a novel ferroportin variant: the c.1502 A>G transition, which changes amino acid 501 from tyrosine to cysteine (p.Y501C). This novel variant was identified in a pedigree originating from Central Italy and, although an intra-familial phenotype heterogeneity was observed, it co-segregated with an iron overload picture similar to that of the HFE-related typical haemochromatosis. In cultured cells, the p.Y501C mutant protein reached the plasma membrane and retained a full iron export ability. By contrast, it was resistant to inhibition by hepcidin. These findings confirm that certain ferroportin mutations compromise the activity of hepcidin in iron homeostasis, mimicking hepcidin deficiency as described in all types of hemochromatosis.

A mutation analysis of the HFE gene followed, when applicable, by sequencing was performed on 47 patients with hereditary haemochromatosis (HH) living in Saguenay-Lac-Saint-Jean. The C282Y and H63D mutations were present on 50% and 20.3% of the HH chromosomes respectively. These frequencies were very different from those found in other populations and could be, at least partially, the result of a founder effect. No new mutation was identified among the remaining 28.1% of the HH chromosomes. Five of the eight probands with no mutation in the HFE gene had a severe and early onset suggestive of juvenile haemochromatosis.