Hereditary Hemochromatosis Type 3, Analysis of M172k Mutational Sequence in A Single Male Patient

2, 3, 4), TFR2 (exons 2, 4, 6) and FPN1 (exon 5) genes were evaluated in 257 patients (194 male and 63 female). Mutations in HFE, TFR2 and FPN1 genes were evaluated with standard kits. Iron overload was checked out through laboratory testing for serum, ferritin and transferrin saturation. In 257 enrolled patients, a single M172K mutation of TFR2 gene in a 33 years old man has been identified, while no other mutations for HFE and FPN1 genes were observed. Although some HH genetic polymorphisms have been identified, TFR2 gene mutation have not been clearly defined.


Introduction
Hereditary Hemochromatosis (HH) is a genetic disease due to an excessive intestinal dietary iron absorption in basolateral surface of enterocytes. HH represents one of the most common genetic disease in North Europe. This suggests that genetic mutation leading to hemochromatosis originally occurred in Celtic populations [1].
In 1865, Trousseau described a new syndrome characterized by diabetes, pigmented liver, cirrhosis and bronze-colored skin.In 1889, Von Recklinghausen coined the term hemochromatosis to connect the symptoms reported, 24 years earlier, by Trousseau to an abnormal iron deposition in tissues and organs. In 1935, Sheldon classed this disease as an inborn error of metabolism [2].
According to Online Mendelian Inheritance in Man (OMIM), 5 types of HH have been identified and classified on the basis of different clinical, biochemical, and genetic characteristics [3]: 1) HH type 1 is due to HFE gene mutations which is linked on chromosome 6. HH type 1 is also known as Classic Hereditary Hemochromatosis and represents the most common genetic iron overload disorder in Caucasian populations [2]. HFE gene encodes for membrane protein which is similar to major histocompatibility class I-like (MHC1). Mutation in HFE gene generates a protein unable to interact with TFR1 protein (transferrin receptor 1). This affects iron overload in liver, heart, pancreas and skin leading to liver damage, myocarditis, diabetes and hypogonadism. The majority of HH type 1 cases (approximately 80%) is homozygous for a mutation linked to the substitution of a tyrosine residue for cysteine at position 282 (C282Y) [3].
2) HH type 2 (juvenile) is considered the most severe form of rare HH. First symptoms of iron overload typically begin during childhood and include low sex-hormones level and heart disease. HH type 2 is divided into two forms: HH type 2A caused by mutation in HJV gene linked on chromosome1; HH type 2B due to HAMP gene mutation linked on chromosome 19. Serum and urinary hepcidin levels are decreased in both mutations.
Juvenile hemochromatosis symptoms are like those seen in HH type 1 and occur at an early age and are usually more severe [4].   for TFR2 gene showed hepcidin down-regulation. This suggest that TFR2 is an essential gene in the pathway of iron homeostasis [9]. Hepcidin is synthesized predominantly in hepatocytes and is considered the principal regulator of iron absorption. Dysregulation of hepcidin production results in a variety of iron disorders.

Hepcidin deficiency is associated with systemic iron overload and
Hereditary Hemochromatosis [8].

Results
In 257 enrolled patients, this test revealed a single M172K mutation only in a 33 years old man; no other mutations for HFE and FPN1 genes, were observed in the same case.

Discussion
HH is the principal cause of systemic iron overload. It is known that HH can be due to different mutations in different genes.
The lack of knowledge and the absence of diagnostic tools make the diagnosis very complex. In this study, the molecular analysis prompts to formulate an early diagnosis of TFR2-related (type 3) HH that increases the chances for successful treatment. This work adds more information about HH type 3 suggesting that M172K mutation could be more frequently involved in systemic primary iron overload than has been thought.