R. K.  Chan

Most inherited diseases caused by single-gene mutations affect relatively few people, but are a major focus of research by scientists seeking to improve outcomes for patients and to learn more about the normal functions of the human body. Why is the study of these monogenic diseases so important?

Monogenic diseases provide a clear link between the disease and the molecule or structure affected by the gene. In the same way, you can prove that a battery supplies electricity for starting your car because removing the battery will prevent your car from starting.

Insights into the mechanisms of iron homeostasis, or how the body maintains just the right level of iron, have come from the study of monogenic diseases such as hereditary hemochromatosis (PMID 16409153, PMID 20542038), an iron overload disease which is included in Pathway’s Pre-Pregnancy Planning Test.

Iron — Necessary for Life, but Also Toxic

Iron readily gains and loses electrons: a property that helps it bind oxygen as a component of the hemoglobin molecule in red blood cells (PMID 17987043). On the other hand, this capacity for electron exchange also means that unbound iron can react with oxygen to produce free radicals that are very damaging to the cell. To prevent formation of free radicals, iron is always bound to a protective protein–ferritin inside the cell and transferrin in the plasma. Iron is also an essential component of the myoglobin in your muscle and of many enzymes including the cytochrome enzymes in your liver.

How is the Level of Iron in the Body Regulated?

The levels of iron in the body must be carefully regulated because too much or too little iron can cause iron overload disease (hemochromatosis) or anemia, respectively (PMID 17987043, PMID 21054916). The excretion of iron is not regulated, so iron homeostasis is maintained by controlling the amount of iron coming into the body. Iron from food enters through the small intestine, where it is absorbed by enterocytes–cells that line the lumen of the duodenum. Iron gets into the bloodstream via a protein in the enterocytes called ferroportin which exports the iron. A peptide hormone from the liver, called hepcidin, downregulates the amount of ferroportin. Thus the overall control of iron metabolism resides in the liver, where the synthesis of hepcidin is regulated in response to inputs about the need for more iron. For example, hypoxia or lack of oxygen signals a need for more red blood cells and reduces the synthesis of hepcidin so ferroportin is allowed to transport more iron into the body. On the other hand, if there is too much iron in the body, the synthesis of hepcidin will be stimulated, so that more ferroportin will be removed, resulting in less iron intake into the body. Hepcidin is synthesized in response to bacterial infections; this suppresses iron uptake and prevents the growth of iron-requiring pathogenic bacteria.

Monogenic diseases affecting iron metabolism

A key mechanism in iron homeostais is the downregulation of ferroportin in enterocytes by the peptide hormone hepcidin. The role of hepcidin and ferroportin in iron homeostasis is supported by the identification of mutations in the genes for hepcidin (HAMP), ferroportin (FPN), and by the identification of mutations in genes (HFE, HFE2, TFR2 and TMPRSS6) which regulate the synthesis of hepcidin (PMID 17987043, PMID 21150441). Mutations in these genes cause diseases of iron metabolism which result in excess iron absorption leading to iron overload or result in iron deficiency leading to anemia. Researchers investigating these genes have concluded that the molecular basis for hemochromatosis is insufficient hepcidin production (PMID 21150441). Mutations in the TMPRSS6 gene that result in too much hepcidin production cause an iron-refractory iron deficiency (IRIDA).

The Two Most Common Hemochromatosis Mutations

The excess iron in hereditary hemochromatosis can damage many organ systems including the liver, skin, pancreas, endocrine glands, joints, and heart. The only way to remove the excess iron is by bloodletting (therapeutic phlebotomy). If such treatment is started in time, the affected individuals will have a normal lifespan. Therefore, early diagnosis is essential.

The Pathway Pre-Pregnancy Planning Kit tests for the C282Y and H63D variants of the HFE gene, which are the most common cause of hereditary hemochromatosis. The C282Y mutation is thought to have originated by chance in a single Celtic (or Viking) ancestor in northwestern Europe about 2000 years ago. Homozygosity for the C282Y mutation is now found in approximately 5 of every 1000 persons of northern European descent. The carrier rate for C282Y is 1 in 9 for Caucasians, 1 in 33 for Hispanics, 1 in 43 for African-Americans, and 1 in 1000 for Asians. The H63D mutation is an older, more prevalent mutation with a worldwide distribution and a carrier rate of 1 in 4 for Caucasians, 1 in 6 for Hispanics, 1 in 17 for African-Americans, and 1 in 12 for Asians. About 60%-90% of individuals with HFE-related hereditary hemochromatosis (HFE-HHC) carry two copies of C282Y. 87% of individuals of European origin with HFE-HHC either carry two copies of the C282Y variant or carry one copy of the C282Y variant and one copy of the H63D variant.

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