HAMP promoter mutation nc.-153C>T in non p.C282Y homozygous patients with iron overload

Abstract

) and the Basque population: contribution of HLA class I molecular markers to their evolutionary history. HAMP promoter mutation nc.-153C>T in non p.C282Y homozygous patients with iron overloadIn a recent paper, Island and colleagues 1 described a heterozygous hepcidin (HAMP) promoter mutation, nc.-153C>T, which in association with HFE p.C282Y homozygosity appeared to lead to very severe iron overload (IO). They demonstrated in vitro that this HAMP mutation decreases transcriptional activity of the hepcidin promoter, alters IL6 total responsiveness and impairs binding of the SMAD protein complex to the BPM-RE.HFE genotypes other than the homozygous p.C282Y (YY) or the compound heterozygous state for the p.C282Y and p.H63D mutations are not considered responsible for causing symptomatic forms of IO. This led us to re-evaluate 30 unrelated patients with non-YY HFE genotype associated with the diagnostic criteria of hemochromatosis who were referred to our laboratory. Among them, 12 were previously reported H63D homozygotes.2 The diagnosis of IO was based on either liver biopsy and/or therapeutic criteria (phlebotomies). Informed written consent was obtained from all patients according to the French regulation.DNA sequencing of the HAMP gene found no mutation in the coding sequence or in the exon-intron junctions of the 30 patients. However, two gene substitutions, a C to T replacement at position -153 upstream of the ATG and a C to T substitution in intron 1 at position -66, 5' to exon 2 (c.91-66C>T, rs#2293689) were identified in 3 patients. Both sequence alterations were found in all 3 patients but we could not confirm whether they were in linkage disequilibrium or whether they were inherited on different chromosomes, as family segregation could not be performed. The patients, 3 white men living in different cities of the Southern part of France, were referred separately by three different physicians. To the best of our knowledge the men are not related. They all had ferritin levels over 1000 μg/L and transferrin saturation over 50%. They had been regularly phlebotomized for more than one year. Two of them, a 75-year old and a 54-year old male respectively, were p.H63D homozygotes ( Table 1). The third patient, diagnosed at 69 years of age, was simply heterozygote for the p.S65C substitution on the HFE gene. His medical record indicated that he had myocardiopathy, cirrhosis and a liver biopsy compatible with the diagnosis of hemochromatosis (Table 1). Two patients had a family history of iron overload. Both substitutions, nc.-153C>T and c.91-66T>C, were also found in one out of 224 unrelated control chromosomes from white individuals of the same region. The iron status of this anonymous control was not available. The HAMP nc.-153C>T mutation was thus present at a high allele frequency (0.05) in this series of non-YY iron loaded patients. It was also found in one control subject, with a low allele frequency of 0.004 in this group (P=0.008). 3 Barton and colleagues4 did not detect HAMP nc.-153C>T in any of 191 HFE...

The role of genetic factors in patients with hepatocellular carcinoma and iron overload – a prospective series of 234 patients

“…The prevalence of this mutation in the general population seems to be low. It was found at an allele frequency of 0.0045 in our region in southern France (27) and was reported at an allele frequency of 0.0049 in healthy individuals from Galicia (Spain) (39). On the other hand, it was neither found in 200 normal chromosomes from Brittany, nor in 785 HEIRS study participants.…”

“…This mutation has been linked to severe IO . We previously showed that the allele frequency of this variant was 0.004 in the population of our area , whereas it was 0.09 among the 13 iron‐overloaded HCC patients of this series ( P = 0.0013). This mutation was also found in one additional patient in the control group of subjects with abnormal iron parameters (allele frequency: 0.028; P = 0.15 when compared to the general population of the area).…”

“…The main finding in the iron-overloaded HCC group was the presence of the HAMP:c-153C>T mutation. We first previously described this mutation in three unrelated patients with severe IO and non-C282Y HFE genotypes (27,38). Island et al (26) found this mutation in a 37 year old C282Y homozygote presenting massive hepatic IO.…”

Inherited or acquired modifiers of iron status may dramatically affect the phenotype in dehydrated hereditary stomatocytosis

“…Genetic modifiers increasing iron stores, such as the presence of the HFE C282Y mutation or a HAMP mutation and possibly gender (male patient 3), were accompanied by high LIC and increased hemolysis . Indeed, heterozygosity for the HFE C282Y mutation (patient 1) and the HAMP :c.‐153C>T mutation (patients 3 & 4) is known contributing factor to IO in association with other genetic or acquired conditions . Patient 3 had a more severe iron overload than patient 2 (his mother) who did not carry the HAMP mutation and than patient 4 (his sister) who did carry the same HAMP mutation but had initially concomitant iron deficiency due to increased gynecological bleeding.…”

“…153C>T mutation (patients3 & 4) is known contributing factor to IO in association with other genetic or acquired conditions 5. Patient 3 had a more severe iron overload than patient 2 (his mother) who did not carry the HAMP mutation and than patient 4 (his sister) who did carry the same HAMP mutation but had initially concomitant iron deficiency due to increased gynecological bleeding.…”