Rh-Null, Regulator Type

A number sign (#) is used with this entry because of evidence that the regulator type of RH-null phenotype is caused by homozygous or compound heterozygous mutation in the RHAG gene (180297) on chromosome 6p12.

Clinical Features

Chown et al. (1972) described the effects of a genetic modifier for the Rh blood groups. Heterozygotes showed weakening of reaction of all Rh antigens. A homozygote also had a weak reaction with anti-U and anti-S, compensated hemolytic anemia, and unconjugated hyperbilirubinemia. The modifier was clearly not linked with the Rh locus. The authors compared this 'modified' phenotype (Rh-mod) with the Rh-null phenotypes that had been described. When homozygous, both the suppressor gene and the Rh amorphic gene (Rh-null) result in anemia, shortened red cell survival, increased fragility, stomatocytes, and increased fetal hemoglobin. Rh antigens constitute part of the red cell membrane.

Nash and Shojania (1987) restudied the woman reported by Chown et al. (1972). The b(51)Cr red cell survival studies showed the spleen to be the preferential site of red cell destruction, and splenectomy produced a dramatic improvement in red cell survival. Her parents were third cousins.

The term 'Rh deficiency syndrome' takes in both the Rh-null and the Rh-mod phenotypes when they are associated with hemolytic anemia (Nash and Shojania, 1987).

In a comprehensive review of the molecular genetics of the Rh blood group antigens, Cartron (1994) indicated that all Rh-null phenotypes that had been investigated appeared to result from transcriptional regulatory mechanisms that were not yet understood. In addition to Rh proteins, several other glycoproteins, such as CD47 (601028), glycophorin B (617923), Duffy (613665), and LW (614088), are absent or severely decreased on these cells. These findings suggested that the Rh proteins are assembled into a multimeric complex with these glycoproteins.

Population Genetics

Nash and Shojania (1987) found reports of 32 cases of Rh-null and 10 cases of Rh-mod. The incidence of the Rh-null phenotype was quoted as being about 1 in 6 million. In most instances the propositi are the offspring of consanguineous marriages.

Molecular Genetics

Red cells lacking Rh blood group antigens were first described by Vos et al. (1961). Rh-null (no Rh antigen on the red cells) exists in 2 forms. One was thought to be due to homozygosity for an amorph allele at the Rh locus (111700). The other is due to homozygosity for a mutation at a locus independent of the Rh locus. The latter form, called the regulator type, is analogous to the Bombay type (616754).

Race and Sanger (1975) pointed out that the regulator cannot be part of the Rh complex: in a family with consanguineous parents, both CDe-cde, one Rh-null sib had to be genetically CDe-cde, because of her children's Rh blood types. Had the regulator been part of, or closely linked to, the Rh locus, she would have been either CDe-CDe or cde-cde. There is apparently heterogeneity in the regulator type of Rh-null.

Cherif-Zahar et al. (1996) showed that the Rh-null phenotype that is unlinked to the Rh locus is caused by mutations in the RH50A gene (RHAG; 180297), located on chromosome 6p. The cell-surface antigen encoded by 3q and not expressed in Rh-null cells probably has no significance to the pathogenesis of the Rh deficiency syndrome (see HISTORY). They noted that a number of components of the multi-subunit complex composed of Rh polypeptides and associated glycoproteins are absent in Rh-null cells.

History

By testing hybrids containing various deletions of chromosome 3, Miller et al. (1987) described an IgM monoclonal antibody, 1D8, that recognizes an antigen coded by a gene that is located in the region 3cen-q22. The monoclonal antibody has been designated MER6.