H/h blood group system Gene locus - FUT1 (H blood group locus) and FUT2 (Secretor locus)
The H antigens are indirect gene products expressed as fucose-containing glycan? units, residing on glycoproteins or glycolipids of erythrocyte membranes or on mucin glycoproteins in secretions.They are the fucosylated glycans that are the direct substrates for glycosyltransferases that give rise to the [[epitope|epitopes] for the A , B and [Lewis Blood Group? Lewis blood group] antigens. Thus, type O erythrocytes typically display the H antigen. Two different, closely linked loci encode the fucosyltransferases? that give rise to the Hh antigens; both loci encode closely homologous alpha 1,2 fucosyltransferases that transfer fucose in an alpha 1-2 linkage to a galactose and result in products whose structure is nearly identical (differ only by a single carbohydrate linkage that differentiates type 1 from type 2 [glycan? glycans]) and constitutes the epitope for the H antigen.
The major difference between the two genes is in their pattern of expression: the FUT1 (H) gene is expressed predominantly in erythroid tissues giving rise to FUT1? (H enzyme) whose products reside on erythocytes, whereas the FUT2? (Se) gene is expressed predominantly in secretory tissues giving rise to FUT2 (Se enzyme) and to products that reside on mucin?s in secretions. When alleles of both genes fail to express active enzymes, individuals bearing them, in homozygous state, lack the substrates for the A or B glycosyltransferases? and do not express the A and B epitopes. Chromosomal location: 19q13.3 for FUT1 and FUT2, which are 35kb apart, in the same orientation, namely, Cent-FUT2-FUT1-Ter; linkage diseequilibrium between the two genes is suggested.
Function of proteins
Primary gene products of functional alleles are closely homologous alpha 1,2 fucosyltransferases? that use nearly identical substrates but are expressed in different tissues (see below). Their products serve as substrates for the glycosyltransferase?s that result in epitopes for the A and B blood group antigens; in addition, the product of FUT2 is a precursor of epitopes resulting in antigens of the Lewis blood group system. Although their precise function is still not known, the fucosylated glycans that are the products of FUT1 and FUT2 may serve as ligands in cell adhesion or as receptors for certain microorganisms.
FUT1 product is expressed predominantly in erythoid tissues, vascular endothelium and primary sensory neurons of peripheral nervous system; the product of FUT2 is expressed in saliva and other exocrine secretions, and in epithelia. Expression of the antigens is known to undergo changes during development, differentiation and maturation. Aberrant glycosylation is often observed in human pre-malignant and malignant cells.
None well documented except in transfusion reactions of Bombay and para-Bombay individuals. They can also trigger hyperacute vascular rejection of transplanted organs in Bombay and para-Bombay recipients. In 1992, Etzioni et al. found two children with a leukocyte adhesion deficiency (LAD II) (), who had "Bombay-like" red cell phenotypes and ABH nonsecretor phenotype in saliva. The condition, identified as a congenital disorder of glycosylation (CDG II) is characterized by mental retardation and severe recurrent infections. The patients lacked all fucosylated antigens in all tissues, but had normal integrin and fucosyltransferase genes (). The condition is due to a defect of the import of GDP-fucose into the Golgi apparatus. Oral fucose administration may result in fucosylation of glycoproteins and amelioration of clinical conditions (,).
About the alleles
A large number of alleles of both FUT1 and FUT2 fail to express active enzymes. The blood group phenotype of individuals bearing such alleles will depend on whether FUT1 or FUT2, or both alleles, are fully or partially inactivated.The H blood group phenotype is uniquely dependent on the expression of FUT1 enzyme, the product of FUT1 gene. Inactive alleles of FUT1 fail to express the H epitopes on red cells and individuals (h), having those alleles, in homozygous state, exhibit either the Bombay or the para-Bombay blood group phenotype. In Bombay indivduals alleles of both FUT1 and FUT2 fail to express the corresponding fucosyltransferases and those individuals lack the ABH antigens on erythrocytes and in secretions. In para-Bombay positive individuals FUT2 is expressed but alleles of FUT1 usually do not result in an active enzyme. There are two different definitions of para-Bombay individuals: those who lack ABO antigens on erythrocytes, but possess them in secretions and those who possess very few ABH antigens on erythrocytes but may or may not possess them on secretions. It is still not clear what determines the levels of H antigen expression on erythrocytes of para-Bombay individuals. However, more recent studies indicate that alleles of FUT1 may result in partially active FUT1s resulting in a weak expression of H on the red cells.
Inactivation of FUT2 does not affect the epitopes present on red cells and such individuals are H-positive; however, their mucins, in secretions, will lack the Se epitope; those individuals are designated "non-secretors" (se); in addition, they will not express the A, B or H epitopes in secretions as they lack the substrates for the respective glycosyltransferases. In addition they will not express the Lewis b antigen whose epitope also is dependent on the expression of FUT2. Individuals are designated "secretors" when they express those epitopes in their secretions. It is important to note that the incidence and the geographic distribution of alleles of FUT1 and FUT2 genes vary greatly. Thus, alleles of FUT1 are rare, occur sporadically and are confined to specific geographically defined regions but the incidence of enzyme-inactivating alleles of FUT2 may be 20 % or higher. In fact, the existence of a human H/h genetic polymorphism was first established by the discovery in India (Bombay) of an individual devoid of the H antigen on red cells, who had antibodies in plasma reacting with all the cells exhibiting the normal red cell ABO phenotypes (). However, this H deficient or Bombay phenotype was rare, since it occurred in about one in 10,000 individuals in India and one per one million individuals in Europe. More recently, a large series of H deficient individuals (~1:1000) was found in a small French Island 800km east of Madagascar, in the Indian Ocean, called Reunion Island. Two distinct phenotypes were found, the classical Bombay phenotype among Tamoul Indian immigrant families and a new, partially deficient phenotype, called the "Reunion" phenotype. The two phenotypes resulted from products, or lack of products, of two different alleles of FUT1 and FUT2 genes; the same and also additional alleles of both FUT1 and FUT2 were documented in other populations, particularly, in Japan, where the incidence of Bombay and para-Bombay individuals was shown to be 1-2 in 300,000. In Taiwan, the para-Bombay phenotype has a frequency of 1:8000.
Observations by the group of Oriol and Mollicone (unpublished and see Fernandez et al.), concerning the possibility of linkage disequilibrium of FUT1 and FUT2 , are noteworthy. The two genes lie in close proximity on chromosome 19q13.3.The observations refer to the joint occurrence of unique sets of mutations in FUT1 and FUT2 , each set occuring in individuals of a certain ethnic group. Thus, 1) in India, the FUT1 mutation 725T>G travels almost always (one exception) with a total deletion of FUT2; 2)in Reunion Island (Caucasian), the major inactivating mutation of FUT1 or 349C>T, travels almost always with the inactivating mutation of FUT2 or 428G>A; 3) the main Oriental inactivating mutations of FUT1 travel almost always with the wild type FUT2. In the list of alleles, for alleles of FUT1, the sequence with acc. no. M35531 ("a" of the 1st. codon 'atg" starts at nt. 104) is taken as reference; for alleles of FUT2 the reference is acc. no. U17894 ("a" of the 1st. codon 'atg" starts at nt. 97).
- This article is licensed under the GNU Free Documentation License. Sections excerpted from Blood Group Antigen Gene Mutation Database. See: Blumenfeld OO, Patnaik SK. Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database. Human Mutation. 2004 Jan; 23(1):8-16. PubMed ID: 14695527