Alternative titles; symbols
HGNC Approved Gene Symbol: RHAG
SNOMEDCT: 115762007, 722125003;
Cytogenetic location: 6p12.3 Genomic coordinates (GRCh38): 6:49,605,175-49,636,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p12.3 | Anemia, hemolytic, Rh-null, regulator type | 268150 | Autosomal recessive | 3 |
| Overhydrated hereditary stomatocytosis | 185000 | Autosomal dominant | 3 |
The RHAG gene encodes the Rh-associated glycoprotein (Rh50), which is necessary for the expression of the Rh antigens and for the proper assembly of RH proteins on the red blood cell membrane (summary by Junca et al., 2021).
The Rh blood group antigens (see 111690) are associated with human erythrocyte membrane proteins of approximately 30 kD, the so-called Rh30 polypeptides. Heterogeneously glycosylated membrane proteins of 50 and 45 kD, the Rh50 glycoproteins, are coprecipitated with the Rh30 polypeptides on immunoprecipitation with anti-Rh-specific mono- and polyclonal antibodies. The Rh antigens appear to exist as a multisubunit complex of CD47 (601028), LW (111250), and glycophorin B (617923), and play a critical role in the Rh50 glycoprotein.
Ridgwell et al. (1992) isolated cDNA clones representing a member of the Rh50 glycoprotein family, the Rh50A glycoprotein. They used PCR with degenerate primers based on the N-terminal amino acid sequence of the Rh50 glycoproteins and human genomic DNA as a template. The cDNA clones containing the full coding sequence of the Rh50A glycoprotein predicted a 409-amino acid N-glycosylated membrane protein with up to 12 transmembrane domains. It showed clear similarity to the Rh30A protein in both amino acid sequence and predicted topology. The findings were considered consistent with the possibility that the Rh30 and Rh50 groups of proteins are different subunits of an oligomeric complex which is likely to have a transport or channel function in the erythrocyte membrane.
Huang (1998) determined the intron/exon structure of the Rh50 gene. The structure of the Rh50 gene is nearly identical to that of the Rh30 gene. Of the 10 exons assigned, conservation of size and sequence was confined mainly to the region from exons 2 to 9, suggesting that RH50 and RH30 were formed as 2 separate genetic loci from a common ancestor via a transchromosomal insertion event.
Crystal Structure
Khademi et al. (2004) determined the crystal structure of the ammonia channel from the Amt/MEP/Rh protein superfamily at 1.35-angstrom resolution. The channel spans the membrane 11 times. Two structurally similar halves span the membrane with opposite polarity. Structures with and without ammonia or methyl ammonia show a vestibule that recruits NH4+/NH3, a binding site for NH4+, and a 20-angstrom-long hydrophobic channel that lowers the NH4+ pKa to below 6 and conducts NH3. Favorable interactions for NH3 were seen within the channel and used conserved histidines. Khademi et al. (2004) concluded that reconstitution of AmtB into vesicles shows that AmtB conducts uncharged ammonia.
By analysis of somatic cell hybrids, Ridgwell et al. (1992) mapped the Rh50A gene to 6p21-qter, indicating that genetic differences in the genes for the Rh30 polypeptide, rather than the Rh50 genes, specify the major polymorphic forms of the Rh antigens, because the Rh blood group maps to chromosome 1, not chromosome 6. Cherif-Zahar et al. (1996) carried out 5 regional assignments of the Rh50 gene by isotopic in situ hybridization and concluded that it maps to 6p21.1-p11, probably 6p12.
The absence of the RhAG and Rh proteins in Rh-null individuals leads to morphologic and functional abnormalities of erythrocytes, known as the Rh-deficiency syndrome. The RhAG and Rh polypeptides are erythroid-specific transmembrane proteins belonging to the same family (36% identity). Marini et al. (1997) and Matassi et al. (1998) found significant sequence similarity between the Rh family proteins, especially RhAG, and Mep/Amt ammonium transporters. Marini et al. (2000) showed that RhAG and also RhGK (605381), a human homolog expressed in kidney cells only, function as ammonium transport proteins when expressed in yeast. Both specifically complement the growth defect of a yeast mutant deficient in ammonium uptake. Moreover, ammonium efflux assays and growth tests in the presence of toxic concentrations of the analog methylammonium indicated that RhAG and RhGK also promote ammonium export. The results provided the first experimental evidence for a direct role of RhAG and RhGK in ammonium transport and were of high interest, because no specific ammonium transport system had been previously characterized in human.
Westhoff et al. (2002) used the Xenopus oocyte expression system to determine the function of Rh and RhAG proteins. They demonstrated expression of fully glycosylated RhAG protein and provided the first direct evidence for RhAG-mediated ammonium uptake.
Ripoche et al. (2004) assayed transport in red blood cells and ghosts from human and mouse genetic variants with defects in RhAG or other components of the Rh complex. They found that the rate constant for methylammonium or ammonium transport directly correlated with the amount of functional RhAG and was unaffected by the amount of Rh, CD47, or LW.
Bruce et al. (2009) expressed RHAG in Xenopus laevis oocytes and observed induction of a monovalent cation leak, with a rise in intracellular Na+ and a fall in intracellular K+ such that after 3 days, intracellular Na+ exceeded intracellular K+. The authors suggested that RHAG has the properties of a cation pathway and may represent a regulated cation channel.
Rh-null, Regulator Type
The Rh-null types Rh-null regulator (RHNR; 268150) and Rh-mod (in which trace amounts of Rh antigens are found), exhibit the same clinical abnormalities associated with chronic hemolytic anemia, stomatocytosis and spherocytosis, reduced osmotic fragility, and increased cation permeability. In addition, Rh-null membranes characteristically have hyperactive membrane ATPases and reduced red cell cation and water content. Cherif-Zahar et al. (1996) proposed that mutant alleles of Rh50 are suppressors of the RH locus and account for most cases of Rh-deficiency. They analyzed the genes and transcripts encoding Rh, CD47, and Rh50 proteins in 5 unrelated Rh-null cases and identified 3 types of Rh50 mutations in the transcripts and genomic DNA from them. The first mutation was observed in homozygous state in 2 apparently unrelated individuals originating from South Africa and involved a 2-bp transversion and a 2-bp deletion, introducing a frameshift after the codon for tyrosine-51 (180297.0001). They stated that, since the Rh50 glycoprotein was not detectable by flow cytometry or Western blot analysis on the red cells of these 2 individuals, it is likely that the predicted truncated Rh50 polypeptide (107 residues instead of 409) from these variants was degraded and not inserted into the membrane. The second mutation consisted of a single-base deletion at nucleotide 1086, resulting in a frameshift after the codon for alanine-362 (180297.0002). The deduced Rh50 protein was 376 amino acids long (instead of 409) and included 14 novel residues at its C terminus. Surprisingly, this mutation was found in the heterozygous state by RFLP analysis. Attempts to amplify the product of the second Rh50 allele were unsuccessful, strongly suggesting that this transcript was either absent or poorly represented in reticulocytes. Cherif-Zahar et al. (1996) assumed that this allele was transcriptionally silent and that the subject's erythrocytes should carry half the normal dose of a truncated Rh50 protein. Interestingly, flow cytometry and Western blot analysis indicated a complete absence of the protein. They noted that RH and Rh50 proteins interact with each other and suggested that the C terminus of Rh50 may stabilize this interaction or may represent a site of protein-protein interaction critical for cell surface expression. The third Rh50 mutation identified by Cherif-Zahar et al. (1996) was a missense mutation caused by a G236A transition (180297.0003). Flow cytometry and Western blot analysis indicated that the mutant protein was expressed at the cell surface at only 20% of the wildtype level.
Cherif-Zahar et al. (1996) provided a diagram of the implication of the 3 mutations in 4 patients with the Rh-null phenotype of the regulator type. In the fifth subject with Rh-null phenotype studied by Cherif-Zahar et al. (1996), all attempts to amplify the Rh50 transcript were unsuccessful, although Rh, CD47, and LW sequences were easily amplified and sequenced from reticulocyte RNAs. This suggested that the Rh50 gene was transcriptionally silent in this variant, as had been observed in 1 allele of the subject with the deletion of nucleotide 1086. Findings in these cases indicated to the authors that Rh antigens are significantly expressed only when Rh50 proteins are present. Cherif-Zahar et al. (1996) stated, however, that the converse is not true; a small amount of Rh50 may reach the cell surface in the absence of Rh proteins as indicated by the Rh-null variant of the silent type. The identification of different Rh50 mutations may account for the well known heterogeneity of Rh-null individuals classified as regulator and Rh-mod types.
Huang et al. (1998) described compound heterozygosity for 2 mutations in the Rh50 glycoprotein gene. An 836G-A mutation in exon 6 resulted in a gly279-to-glu substitution, changing a central amino acid of the transmembrane segment 9 (180297.0004). While cDNA analysis showed expression of the 836A allele only, genomic studies showed the presence of both 836A and 836G alleles. A detailed analysis of gene organization led to the identification in the 836G allele of a defective donor splice site, caused by a G-to-A mutation in the invariant GT element of the splice donor site of intron 1 (180297.0005).
The Rh-mod syndrome is a rare genetic disorder thought to result from mutations at a 'modifier' separate from the suppressor underlying the regulator type of Rh-null disease, i.e., the RHAG gene. Huang et al. (1999) studied this disorder in a Jewish family with a consanguineous background and analyzed RH and RHAG, the 2 loci that control Rh-antigen expression and Rh-complex assembly. Despite the presence of a d (D-negative) haplotype, no other gross alteration was found at the RH locus, and cDNA sequencing showed a normal structure of D, Ce, and ce Rh transcripts in family members. However, analysis of the RHAG transcript identified a single G-to-T transversion in the initiation codon, causing a missense amino acid change: ATG (met) to ATT (ile) (180297.0007).
In a 14-year-old Argentinean girl with RH-mod phenotype, in whom sequencing of RHD (111680) and RHCE (111700) showed no changes, Mufarrege et al. (2020) detected homozygosity for a c.920C-T transition in exon 6 of the RHAG gene resulting in a ser307-to-phe (S307F; 180297.0013) substitution. Her parents and sister were heterozygous for the variation.
In a 47-year-old woman with RH-null phenotype of the regulator type, Junca et al. (2021) found homozygosity for a missense mutation (G182S; 180297.0014) in the RHAG gene.
Overhydrated Hereditary Stomatocytosis
In 7 kindreds with overhydrated hereditary stomatocytosis (OHST; 185000), Bruce et al. (2009) analyzed the candidate gene RHAG and identified heterozygosity for the same missense mutation in affected individuals from 6 of the families (F65S; 180297.0011). The remaining patient was heterozygous for a different missense mutation (I61R; 180297.0012). Expression in Xenopus laevis oocytes demonstrated that the mutant proteins induced a large monovalent cation leak.
Stewart et al. (2011) identified heterozygosity for the RHAG F65S mutation in 4 unrelated individuals with OHST. Noting that 17 of 18 OHST patients with published RHAG mutations harbored a heterozygous F65S mutation, Stewart et al. (2011) concluded that F65S represents a mutation hotspot for RHAG-associated OHST. Expressed in Xenopus oocytes, the F65S mutant exhibited both the gain-of-function phenotypes of enhanced currents and enhanced Rb+ and Li+ permeabilities (likely endogenous) as well as the loss-of-function phenotype of severely decreased methylammonium chloride (MA/MA+) transport with altered properties. These findings, together with previous data, suggested that the increased cation permeabilities accompanying overexpression of wildtype and mutant RHAG polypeptides represent secondarily altered regulation of endogenous permeability pathways.
In a 3-generation family with OHST, Shmukler et al. (2013) identified heterozygosity for the F65S mutation in the RHAG gene that segregated with disease.
Heitman and Agre (2000) diagrammed the phylogenetic tree of multiple sequences from human Rh blood group antigens, human Rh glycoproteins, nonhuman sequences with Rh homology, and ammonium transporters from yeast, bacteria, plants, and worms.
Goossens et al. (2009) found that Rhd (111680) -/- and Rhag -/- single-knockout mice and Rhd -/- Rhag -/- double-knockout mice were indistinguishable from wildtype mice at a gross phenotypic level, with normal growth, development, and fertility, and no differences in basic plasma and urine chemistry. Both Rhd -/- and Rhag -/- mice showed slightly increased iron levels. Ferritin levels exhibited a tendency toward decrease in Rhag -/- mice of both sexes and in female Rhd -/- mice, whereas a statistically significant trend towards a decrease in transferrin levels was seen only in male Rhag -/- mice. However, double-knockout mice showed no significant changes in iron, transferrin, or ferritin levels. Flow cytometric analysis showed a loss of Rh protein expression and approximately 70% reduction of Rhag glycoprotein expression in red blood cells (RBCs) from Rhd -/- mice. RBCs from Rhag -/- mice also lost Rh protein expression. Rhag +/- mice displayed an approximately 50% decrease in Rhag expression, with a corresponding 50% reduction in Rh protein expression in RBCs. Western blot analysis revealed absence of Rh protein and Icam4 (614088) in RBCs from Rhd -/- or Rhag -/- mice, and expression of these proteins in double-knockout mice was the same as in single knockouts. Ammonium and methylammonium transport was reduced in red cell ghosts from Rhag -/- mice, and Icam4-dependent adhesion of RBCs to endothelial cells was defective in Rhd -/- and Rhag -/- mice. However, Rhd -/- and Rhag -/- mice showed no major alterations in erythrocyte parameters, blood cell count, blood cell morphology, or histology of spleen and bone marrow, and stress erythropoiesis was not modified in double-knockout mice.
In 2 apparently unrelated subjects (S.F. and J.L.) with hemolytic anemia originating from South Africa with Rh-null phenotype of the regulator type (RHNR; 268150), Cherif-Zahar et al. (1996) found homozygosity for a change of RHAG nucleotides 154-157 from CCTC to GA (a 2-bp transversion and a 2-bp deletion; c.154_157delinsGA), introducing a frameshift after the codon for tyrosine-51 and resulting in a premature stop codon at codon 107.
In a subject (T.B) with hemolytic anemia and Rh-null of the regulator type (RHNR; 268150), Cherif-Zahar et al. (1996) found heterozygosity for a deletion of adenine-1086 which introduced a frameshift after the codon for alanine-362 and resulted in a premature stop codon at codon 376. Attempts to isolate the product of the second RHAG allele were unsuccessful. No Rh50 protein expression was detected in the patient.
In a subject (V.L.) with Rh-null of the 'mod' type (268150), Cherif-Zahar et al. (1996) found a missense mutation, ser79 to asn, caused by a G-to-A transition at nucleotide 236. The other allele was apparently silent.
Hyland et al. (1998) reported molecular findings in the case of an Rh-null (RHNR; 268150) individual, Y.T., for whom the regulator or amorph type had never been formally documented, although the donor's cells were used in several biochemical studies. Preliminary family studies showed that functional D and C antigens were transmitted from Y.T. to 3 children, suggesting that Y.T. belonged to the regulator type. Molecular studies showed that Y.T. inherited the mutation from her mother and was a compound heterozygote (composite heterozygote in the terminology of Hyland et al., 1998), carrying 1 mutant Rh50 allele and 1 transcriptionally silent Rh50 allele. The Rh50 mRNA was found to contain an 836G-A transition yielding a missense and nonconservative gly279-to-glu (G279E) amino acid substitution within a predicted hydrophobic domain of the membrane protein. Y.T. was found by study of genomic DNA to be carrying both an 836A allele and an 836G allele but only the 836A sequence was represented in cDNA, indicating that the 836G allele was silent.
Huang et al. (1998) demonstrated compound heterozygosity of the Rh50 gene as the basis of the Rh-null phenotype. One mutation was an 836G-A mutation resulting in a missense change, gly279 to glu, in exon 6. The other mutation was a change of the invariant GT element of the splice donor site of intron 1 to AT. The blood sample in this case was from a female proband (Y.T.) of Australian origin. Serologic tests confirmed the null status of Rh antigens (D-C-E-c-e- and Rh17-).
For discussion of the G-to-A transition at the +1 position of intron 1 of the RHAG gene (IVS1G-A+1) that was found in compound heterozygous state in a patient with RH-null, regulator type (RHNR; 268150) by Huang et al. (1998), see 180297.0004.
The same mutation was found by Cherif-Zahar et al. (1998) in homozygous state in a patient in California with Rh-null of the regulator type (RHNR; 268150).
Cherif-Zahar et al. (1998) described splicing mutations in the Rh50 gene in 2 unrelated patients with the 'typical Rh-null syndrome' (RHNR; 268150). The first mutation affected the invariant G residue of the 3-prime acceptor splice site of intron 6, causing the skipping of the downstream exon and the premature termination of translation. The second mutation occurred at the first base of the 5-prime donor splice site of intron 1 (180297.0005). Both of these mutations were found in homozygous state.
In a Jewish family of Russian origin with a consanguineous background, Huang et al. (1999) found that the basis of the Rh-mod syndrome (268150) was a met-to-ile mutation in the initiation codon of the RHAG transcript. This point mutation occurred in the genomic region spanning exon 1 of RHAG. The presence of the mutation in the mother and 2 children was confirmed by SSCP analysis. Although blood typing showed a very weak expression of Rh antigens, immunoblotting barely detected the Rh proteins in Rh-mod membrane. In vitro transcription-coupled translation assays showed that the initiator mutants of Rh-mod, but not those of the wildtype, could be translated from ATG codons downstream. The findings pointed to incomplete penetrance of the Rh-mod mutation, in the form of 'leaky' translation, leading to some posttranslational defects affecting the structure, interaction, and processing of Rh50 glycoprotein. The mother in this pedigree (S.M.) and her brother (S.S.) were first described as cases of Rh-null. S.M. had a well-compensated hemolytic anemia, whereas S.S. had a normal hematologic count with numerous spherocytes and stomatocytes after splenectomy. S.M. was found to be homozygous for the mutation; SS was deceased at the time of study. The 2 children of S.M. were heterozygotes.
In 1 patient with Rh-null disease of the regulator type (RHNR; 268150), Huang (1998) detected a shortened Rh50 transcript lacking the sequence of exon 7. They identified a G-to-A transition at the +1 site of IVS7 in homozygosity in this patient. This splicing mutation caused not only a total skipping of exon 7 but also a frameshift and premature chain termination. Thus, the deduced translation product contained 351 instead of 409 amino acids, with an entirely different C-terminal sequence following thr315.
Huang et al. (1999) demonstrated that a Japanese patient with Rh-null hemolytic anemia of the regulator type (RHNR; 268150) was homozygous for 2 cis mutations in the RHAG gene: in exon 6, G-to-A transitions, GTT to ATT and GGA to AGA, which caused val270-to-ile and gly280-to-arg substitutions, respectively.
In a Japanese patient with Rh-null hemolytic anemia of the regulator type (RHNR; 268150), Huang et al. (1999) identified a G-to-T transversion in exon 9 of the RHAG gene, converting GGT (gly) to GTT (val) at codon 380 in the transmembrane-12 segment. The transversion, which was located at the +1 position of exon 9, had also affected pre-mRNA splicing and caused partial exon skipping. Despite a structurally normal Rh antigen locus, hemagglutination and immunoblotting showed no expression of Rh antigens or proteins.
In affected individuals from 6 kindreds with overhydrated hereditary stomatocytosis (OHST; 185000), including 5 which were previously reported (Stockport, Lock et al., 1961; Brighton, Meadow, 1967; Grenoble, Morle et al., 1989; and Albuquerque and Toulouse, Fricke et al., 2004), Bruce et al. (2009) identified heterozygosity for a c.194T-C transition in exon 2 of the RHAG gene, resulting in a phe65-to-ser (F65S) substitution at a highly conserved residue. The mutation segregated with disease in 3 families for which DNA was available and was not found in 56 controls. Expression in Xenopus laevis oocytes demonstrated that the F65S mutant induced a large monovalent cation leak that was 6 times that of wildtype.
Stewart et al. (2011) identified heterozygosity for the F65S mutation in 4 unrelated individuals with overhydrated stomatocytosis, including the patient originally studied by Mentzer et al. (1975). The mutation was shown to have arisen de novo in the 1 patient for whom parental DNA was available. Stewart et al. (2011) concluded that F65S represents a mutation hotspot for RHAG-associated OHST. Expressed in Xenopus oocytes, the F65S mutant exhibited both the gain-of-function phenotypes of enhanced currents and enhanced Rb(+) and Li(+) permeabilities (likely endogenous) as well as the loss-of-function phenotype of severely decreased methylammonium chloride (MA/MA+) transport with altered properties.
Using a pH-sensitive probe, Genetet et al. (2012) resealed ghosts from the erythrocytes of 4 OHST patients with the F65S mutation ('Nancy' patient, Bruce et al., 2009; father and daughter of 'Grenoble' kindred, Morle et al., 1989; and 'Toulouse' patient from family 'B' of Fricke et al., 2004) and submitted them to ammonium gradients. The authors observed that alkalinization rate constant values decreased by approximately 50% in OHST erythrocytes compared to controls, and concluded that this decrease is related to loss of function of the F65S-mutated RHAG monomer.
In a mother and daughter with OHST, previously reported by Eber et al. (1989), Shmukler et al. (2013) identified heterozygosity for the F65S mutation in the RHAG gene. The mutation was also present in the daughter's affected son, but was not found in 3 unaffected family members. The authors noted that in the affected daughter, an RHAG polymorphism (rs9473627) inherited from her unaffected father severely reduced the PCR amplification of the wildtype allele relative to the mutant allele, resulting in a 'genetically improbable' indication of homozygosity when using the 'I3R1' oligonucleotide. PCR amplification using a different flanking oligonucleotide revealed the genetically appropriate heterozygosity for F65S in the daughter.
In a female patient of Somali descent (designated 'Harrow') with overhydrated stomatocytosis (OHST; 185000), previously reported by Fricke et al. (2004), Bruce et al. (2009) identified heterozygosity for a c.182T-G transversion in exon 2 of the RHAG gene, resulting in an ile61-to-arg (I61R) substitution at a highly conserved residue. The mutation was not found in 56 controls. Expression in Xenopus laevis oocytes demonstrated that the I61R mutant induced a large monovalent cation leak that was 6 times that of wildtype.
In a 14-year-old Argentinean girl with RH-mod phenotype (268150) who presented with hemolytic anemia and respiratory distress, Mufarrege et al. (2020) detected homozygosity for a c.920C-T transition in exon 6 of the RHAG gene resulting in a ser307-to-phe (S307F; 180297.0013) substitution. Serologic analysis indicated an extremely low level of D and C antigens on the erythrocyte membrane. Low expression of RHAG was also found through the anti-RHAG agglutination assay. Her RH alleles were RHD*01, RHCE*Ce. The c.920C-T RHAG allele was designated RHAG*01M.12 by the International Society of Blood Transfusion (ISBT).
In a 47-year-old woman with RH-null phenotype of the regulator type (RHNR; 268150), Junca et al. (2021) found homozygosity for a c.544G-A transversion (c.544G-A, chr6.49,583,433C-T, GRCh38) in exon 4 of the RHAG gene resulting in a gly182-to-ser (G182S) amino acid substitution in the sixth transmembrane segment of the glycoprotein.
Bruce, L. J., Guizouarn, H., Burton, N. M., Gabillat, N., Poole, J., Flatt, J. F., Brady, R. L., Borgese, F., Delaunay, J., Stewart, G. W. The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein. Blood 113: 1350-1357, 2009. [PubMed: 18931342] [Full Text: https://doi.org/10.1182/blood-2008-07-171140]
Cherif-Zahar, B., Matassi, G., Raynal, V., Gane, P., Delaunay, J., Arrizabalaga, B., Cartron, J.-P. Rh-deficiency of the regulator type caused by splicing mutations in the human RH50 gene. Blood 92: 2535-2540, 1998. [PubMed: 9746795]
Cherif-Zahar, B., Raynal, V., Gane, P., Mattei, M.-G., Bailly, P., Gibbs, B., Colin, Y., Cartron, J.-P. Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency. Nature Genet. 12: 168-173, 1996. [PubMed: 8563755] [Full Text: https://doi.org/10.1038/ng0296-168]
Eber, S. W., Lande, W. M., Iarocci, T. A., Mentzer, W. C., Hohn, P., Wiley, J. S., Schroter, W. Hereditary stomatocytosis: consistent association with an integral membrane protein deficiency. Brit. J. Haemat. 72: 452-455, 1989. [PubMed: 2765409] [Full Text: https://doi.org/10.1111/j.1365-2141.1989.tb07731.x]
Fricke, B., Jarvis, H. G., Reid, C. D. L., Aguilar-Martinez, P., Robert, A., Quittet, P., Chetty, M., Pizzey, A., Cynober, T., Lande, W. F., Mentzer, W. C., von During, M., Winter, S., Delaunay, J., Stewart, G. W. Four new cases of stomatin-deficient hereditary stomatocytosis syndrome: association of the stomatin-deficient cryohydrocytosis variant with neurological dysfunction. Brit. J. Haemat. 125: 796-803, 2004. [PubMed: 15180870] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.04965.x]
Genetet, S., Ripoche, P., Picot, J., Bigot, S., Delaunay, J., Armari-Alla, C., Colin, Y., Mouro-Chanteloup, I. Human RhAG ammonia channel is impaired by the Phe65Ser mutation in overhydrated stomatocytic red cells. Am. J. Physiol. Cell Physiol. 302: C419-C428, 2012. [PubMed: 22012326] [Full Text: https://doi.org/10.1152/ajpcell.00092.2011]
Goossens, D., Trinh-Trang-Tan, M.-M., Debbia, M., Ripoche, P., Vilela-Lamego, C., Louache, F., Vainchenker, W., Colin, Y., Cartron, J.-P. Generation and characterization of Rhd and Rhag null mice. Brit. J. Haemat. 148: 161-172, 2009. [PubMed: 19807729] [Full Text: https://doi.org/10.1111/j.1365-2141.2009.07928.x]
Heitman, J., Agre, P. A new face of the rhesus antigen. Nature Genet. 26: 258-259, 2000. [PubMed: 11062455] [Full Text: https://doi.org/10.1038/81532]
Huang, C.-H., Cheng, G., Liu, Z., Chen, Y., Reid, M. E., Halverson, G., Okubo, Y. Molecular basis for Rh-null syndrome: identification of three new missense mutations in the Rh50 glycoprotein gene. Am. J. Hemat. 62: 25-32, 1999. [PubMed: 10467273] [Full Text: https://doi.org/10.1002/(sici)1096-8652(199909)62:1<25::aid-ajh5>3.0.co;2-k]
Huang, C.-H., Cheng, G.-J., Reid, M. E., Chen, Y. Rh(mod) syndrome: a family study of the translation-initiator mutation in the Rh50 glycoprotein gene. Am. J. Hum. Genet. 64: 108-117, 1999. [PubMed: 9915949] [Full Text: https://doi.org/10.1086/302215]
Huang, C.-H., Liu, Z., Cheng, G., Chen, Y. Rh50 glycoprotein gene and Rh(null) disease: a silent splice donor is trans to a gly279-to-glu missense mutation in the conserved transmembrane segment. Blood 92: 1776-1784, 1998. [PubMed: 9716608]
Huang, C.-H. The human Rh50 glycoprotein gene: structural organization and associated splicing defect resulting in Rh-null disease. J. Biol. Chem. 273: 2207-2213, 1998. [PubMed: 9442063] [Full Text: https://doi.org/10.1074/jbc.273.4.2207]
Hyland, C. A., Cherif-Zahar, B., Cowley, N., Raynal, V., Parkes, J., Saul, A., Cartron, J. P. A novel single missense mutation identified along the RH50 gene in a composite heterozygous Rh(null) blood donor of the regulator type. Blood 91: 1458-1463, 1998. [PubMed: 9454778]
Junca, T. G., Pinilla, J. J., Sanjuanelo, M., Lopez, K., Dezan, M. R., Peron, A. C., Oliveira, V. B., Conrado, M. C. A. V., Rocha, V., Mendrone-Junior, A., Dinardo, C. L. A novel mutation in RHAG causing Rhnull phenotype in Colombia. Transfusion 61: E62-E64, 2021. [PubMed: 34309026] [Full Text: https://doi.org/10.1111/trf.16596]
Khademi, S., O'Connell, J., III, Remis, J., Robles-Colmenares, Y., Miercke, L. J. W., Stroud, R. M. Mechanism of ammonia transport by Amt/MEP/Rh: Structure of AmtB at 1.35 A. Science 305: 1587-1594, 2004. [PubMed: 15361618] [Full Text: https://doi.org/10.1126/science.1101952]
Lock, S. P., Smith, R., Hardisty, R. M. Stomatocytosis: a hereditary red cell anomaly associated with haemolytic anaemia. Brit. J. Haemat. 7: 303-314, 1961. [PubMed: 13762977] [Full Text: https://doi.org/10.1111/j.1365-2141.1961.tb00341.x]
Marini, A. M., Urrestarazu, A., Beauwens, R., Andre, B. The Rh (rhesus) blood polypeptides are related to NH4+ transporters. Trends Biochem. Sci. 22: 460-461, 1997. [PubMed: 9433124] [Full Text: https://doi.org/10.1016/s0968-0004(97)01132-8]
Marini, A.-M., Matassi, G., Raynal, V., Andre, B., Cartron, J.-P., Cherif-Zahar, B. The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast. Nature Genet. 26: 341-344, 2000. [PubMed: 11062476] [Full Text: https://doi.org/10.1038/81656]
Matassi, G., Cherif-Zahar, B., Raynal, V., Rouger, P., Cartron, J. P. Organization of the human RH50A gene (RHAG) and evolution of base composition of the RH gene family. Genomics 47: 286-293, 1998. [PubMed: 9479501] [Full Text: https://doi.org/10.1006/geno.1997.5112]
Meadow, S. R. Stomatocytosis Proc. R. Soc. Med. 60: 13-14, 1967. [PubMed: 6018468]
Mentzer, W. C., Jr., Smith, W. B., Goldstone, J., Shohet, S. B. Hereditary stomatocytosis: membrane and metabolic studies. Blood 46: 659-669, 1975. [PubMed: 1174702]
Morle, L., Pothier, B, Alloisio, N., Feo, C., Garay, R., Bost, M., Delaunay, J. Reduction of membrane band 7 and activation of volume stimulated (K+,Cl-)-cotransport in a case of congenital stomatocytosis. Brit. J. Haemat. 71: 141-146, 1989. [PubMed: 2917122] [Full Text: https://doi.org/10.1111/j.1365-2141.1989.tb06288.x]
Mufarrege, N., Franco, N., Trucco Boggione, C., Arnoni, C., de Paula Vendrame, T., Bartoli, S., Ensinck, A., Principi, C., Lujan Brajovich, M., Mattaloni, S., Riquelme, B., Biondi, C., Castilho, L., Cotorruelo, C. Extensive clinical, serologic and molecular studies lead to the first reported Rhmod phenotype in Argentina. Transfusion 60: 1373-1377, 2020. [PubMed: 32378229] [Full Text: https://doi.org/10.1111/trf.15792]
Ridgwell, K., Spurr, N. K., Laguda, B., MacGeoch, C., Avent, N. D., Tanner, M. J. Isolation of cDNA clones for a 50 kDa glycoprotein of the human erythrocyte membrane associated with Rh (rhesus) blood-group antigen expression. Biochem. J. 287: 223-228, 1992. [PubMed: 1417776] [Full Text: https://doi.org/10.1042/bj2870223]
Ripoche, P., Bertrand, O., Gane, P., Birkenmeier, C., Colin, Y., Cartron, J.-P. Human Rhesus-associated glycoprotein mediates facilitated transport of NH3 into red blood cells. Proc. Nat. Acad. Sci. 101: 17222-17227, 2004. [PubMed: 15572441] [Full Text: https://doi.org/10.1073/pnas.0403704101]
Shmukler, B. E., Mukodzi, S., Andres, O., Eber, S., Alper, S. L. Autosomal dominant overhydrated stomatocytosis associated with the heterozygous RhAG mutation F65S: a case of missed heterozygosity due to allelic dropout. Brit. J. Haemat. 161: 602-604, 2013. [PubMed: 23406318] [Full Text: https://doi.org/10.1111/bjh.12261]
Stewart, A. K., Shmukler, B. E., Vandorpe, D. H., Rivera, A., Heneghan, J. F., Li, X., Hsu, A., Karpatkin, M., O'Neill, A. F., Bauer, D. E., Heeney, M. M., John, K., Kuypers, F. A., Gallagher, P. G., Lux, S. E., Brugnara, C., Westhoff, C. M., Alper, S. L. Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S. Am. J. Physiol. Cell Physiol. 301: C1325-C1343, 2011. [PubMed: 21849667] [Full Text: https://doi.org/10.1152/ajpcell.00054.2011]
Westhoff, C. M., Ferreri-Jacobia, M., Mak, D.-O. D., Foskett, J. K. Identification of the erythrocyte Rh blood group glycoprotein as a mammalian ammonium transporter. J. Biol. Chem. 277: 12499-12502, 2002. [PubMed: 11861637] [Full Text: https://doi.org/10.1074/jbc.C200060200]