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Non-erythroid Rh products

About 10 years ago, C. H. Huang and his group demonstrated the existence of two non-erythroid homologues of RHAG in human and mouse non-erythroid tissues. The genes were named RHBG and RHCG in man and Rhbg and Rhcg in the mouse. In both mice and man the genes show a high level of homology tp each other and to RHAG. Thus, at the protein level RhBG and RhCG show 52.4% identity, and both proteins show about 50% identity to the erythroid RhAG. A similar level of identity was shown for mouse Rhbg and Rhcg and the identity to Rhag is about 45% for both mouse proteins. Homology to sequences of homologous proteins of mammals, primitive organisms and lower vertebrates was observed. Sequence alignment of a over 10O RHag, RHbg and RHcg protein homologues from a wide variety of 41 species revealed a consensus primary structure and thus a common topologic model, including the conservation of transmembrane domains, the distribution of charged amino acids and the variation of surface loops on either side of the lipid bilayer.

In contrast to RhAG and Rh30 whose expression is confined to erythroid lineages, RhBG and RhCG are expressed in many tissues and are relatively late onset in both species. Both proteins are abundantly expressed in kidney, but appear to reside in different anatomic structures: Rhbg in convoluted tubules and Henle's loop, whereas Rhcg is concentrated mainly in the collecting ducts. lso, expression in other tissues is distinct, RhBG/Rhbg being expressed predominantly in liver, skin and ovary, whereas RhCG/Rhcg is highly expressed in testis, and moderately in brain, pancreas or prostate.

RHBG and RHCG genes are located on the long arm of chromosomes 1q21.3 and 15q25 respectively.

The function of Rhag, Rhbg and Rhcg is still not clear but their ancient origin, broad eukaryotic occurrence and organ-specific expression suggest that this family of proteins plays a central role in cell and organ homeostasis. Their role as ammonium transporters (Amt) has been proposed by Marini et al. However, S. Kustu and her group showed that the Rh protein expressed in a green algea may function as a gas channel for carbon dioxide. Even though such studies have continued extensively over these last ten years, the knowledge of the function and substrate specificity of these proteins is still not complete. A more recent evolutionary history (Huang and his group), using bioinformatics and phylogenetics as tools, and based on sequences from 41 species from bacterium to man, suggests that Amt and Rh families are distant relatives showing independent evolutionary pathways. The conclusion is that Rh proteins have evolved to acquire a different function from Amt and may serve as carbon dioxide channels under normal physiological conditions.

Literature reference

Huang and Ye, Cell Mol. Life Sci. 67, 2010, 1203; Huang and Peng, PNAS USA. 102, 2005, 15512; Westhoff et al., J. Biol. Chem. 277, 12499, 2002; Soupene et al., PNAS USA. 99, 2002, 3926; Liu et al., J Biol. Chem. 276, 1424, 2001; Huang and Liu, Blood Cells Mol. Dis. 27, 90, 2001; Liu et al., J. Biol. Chem. 275, 25641, 2000; Marini et al., Nat. Genet. 26, 341, 2000.

Non-erythroid Rh homologs
Gene Accession number Reference
RHBG AF193807 Liu et al.
RHCG AF193809 Liu et al.
Rhbg AF193808 Liu et al.
Rhcg AF193810 Liu et al.


Olga. O. Blumenfeld, Ph.D, Dept. of Biochemistry, Albert Einstein College of Medicine, New York, N.Y.,10461, USA. Email -

Updated February, 2012

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