| *300034 | |||||||||||||||||||||||||||||||||||||||||||||
| ANGIOTENSIN II RECEPTOR, TYPE 2; AGTR2 | |||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: AGTR2 | |||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: Xq23 Genomic coordinates (GRCh37): X:115,301,957 - 115,306,224 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||
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| Cloning | |||||||||||||||||||||||||||||||||||||||||||||
| Koike et al. (1994) isolated the AGTR2 gene from a human genomic DNA library of adult female leukocytes. The primary structure deduced from the nucleotide sequence of this putative coding region contains 363 amino acid residues and is highly homologous to the sequences of the rat and mouse protein. Northern blot analysis demonstrated a 3.0-kb mRNA in human fetal lung and kidney and in human adult lung. By Northern blot analysis of RNA from human brain, Vervoort et al. (2002) showed that the AGTR2 transcript was expressed largely in the cerebellum. | |||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||||||||||||||
| Yamada et al. (1996) noted that the AT2 receptor is abundantly expressed in fetus but scantily in adult tissues except brain, adrenal medulla, and atretic ovary. The authors demonstrated that this receptor mediates programmed cell death (apoptosis). They observed this effect in a rat pheochromocytoma cell line and a mouse fibroblast cell line, which express abundant AT2 receptor but not AT1 receptor (AGTR1; 106165). The cellular mechanism appeared to involve the dephosphorylation of mitogen-activated protein kinase (176872). Yamada et al. (1996) hypothesized that this apoptotic function of the AT2 receptor may play an important role in developmental biology and pathophysiology. Using a yeast 2-hybrid assay, Nouet et al. (2004) found that mouse Atip1 (MTUS1; 609589) interacted with the intracellular C-terminal tail of Agtr2, but not with several other receptors, including Agtr1. The C-terminal coiled coil domain of Atip1 mediated the interaction. Ectopic expression of Atip1 in eukaryotic cells led to inhibition of insulin (INS; 176730), basic FGF (FGF2; 134920), and EGF (131530)-induced ERK2 (MAPK1; 176948) activation and DNA synthesis, and it attenuated insulin receptor (INSR; 147670) autophosphorylation in the same way as Agtr2. The inhibitory effects of Atip1 required expression, but not ligand activation, of Agtr2, and inhibition was further increased in the presence of angiotensin II (see 106150), indicating that ATIP1 and AGTR2 cooperate to trans-inactivate receptor tyrosine kinases. In human coronary microarteries obtained from heart-beating organ donors who died of noncardiac causes, Batenburg et al. (2004) observed that AT2 receptor blockade increased the maximal contractile response to angiotensin II, indirectly demonstrating that AT2 receptor stimulation counteracts AT1 receptor-mediated vasoconstriction. During AT1 receptor blockade, angiotensin II relaxed preconstricted microarteries; this effect was abolished by AT2 receptor blockade. Radioligand binding studies and RT-PCR confirmed the expression of AGTR2 in human coronary microarteries. Batenburg et al. (2004) concluded that in coronary microarteries, the net contractile effect of angiotensin II is determined by the magnitude of the response mediated through AT1 (contraction) and AT2 (relaxation) receptors. Albumin (ALB; 103600) endocytosis in renal proximal tubule cells through a clathrin- and receptor-mediated mechanism initiates or promotes tubule-interstitial disease in several pathophysiologic conditions. Using LLC-PK1 porcine proximal tubule cells, Caruso-Neves et al. (2005) showed that angiotensin II increased albumin endocytosis through Agtr2-mediated activation of protein kinase B (AKT1; 164730) in the plasma membrane, which depended on the basal activity of phosphatidylinositol 3-kinase (see 601232). | |||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||||||||||||||
| Koike et al. (1994) determined that the putative coding region of the AGTR2 gene is intronless. Vervoort et al. (2002) stated that the AGTR2 gene contains 3 exons spanning about 5 kb of genomic DNA. The first 2 exons encode a 5-prime untranslated region, and exon 3 encodes the AGTR2 protein. | |||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||
| By studies of a human/rodent somatic cell hybrid panel, Koike et al. (1994) assigned the AGTR2 gene to the X chromosome. The rat homolog is also situated on the X chromosome in that species. Lazard et al. (1994) used isotopic in situ hybridization to assign the AGTR2 gene to Xq24-q25 and the mouse homolog to the X chromosome in region A2-A4. By fluorescence in situ hybridization, Chassagne et al. (1995) assigned the AGTR2 gene to Xq22-q23. Tissir et al. (1995) used the same method to map AGTR2 to Xq22. | |||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||
| Nishimura et al. (1999) reported that mice carrying the angiotensin type-2 receptor gene that is inactivated by gene targeting have phenotypes that remarkably resemble human congenital anomalies of the kidney and urinary tract. These mice, like most children with congenital anomalies of the kidney and urinary tract, lack other somatic anomalies, and inheritance does not follow a typical mendelian pattern. In both rodents and humans, the angiotensin type-2 receptor gene is on the X chromosome. Nishimura et al. (1999) showed that in humans a large fraction of the general population carry a functionally significant mutation in the AGTR2 gene (an A-to-G transition in the lariat branchpoint motif of intron 1, which perturbs AGTR2 mRNA splicing efficiency) and that a remarkably strong association exists between the incidence of congenital anomalies of the kidney and urinary tract and the mutation. They found that 10 of 13 Caucasian patients (77%) (p = 0.034) with ureteropelvic junction stenosis or atresia were hemizygous for the A-to-G transition. In addition, 17 of 23 (74%) (p = 0.026) Caucasian German males with ureteropelvic junction stenosis or atresia were also hemizygous for the A-to-G transition. DNA from 31 American and 24 German unaffected male controls showed the A-to-G mutation in 42% of alleles. The AGTR2 mutation in intron 1 could therefore be a risk factor for the development of ureteropelvic junction stenosis or atresia. The study of Nishimura et al. (1999) further documented that normal development of the kidney and urinary tract is accompanied by timely apoptosis of the undifferentiated mesenchymal cells that initially occupy the metanephros and densely surround the Wolffian duct and ureter. Delay in this apoptosis may lead to the diverse anatomical abnormalities. Vervoort et al. (2002) screened affected males from 33 families with possible X-linked MR but no definitive linkage data, and a large cohort of 552 unrelated male patients with MR of unknown cause but negative for the FMR1 expansion. Eight of the 590 unrelated male patients with MR were found to have sequence changes in the AGTR2 gene, including 1 frameshift and 3 missense mutations. Five of 9 patients with AGTR2 mutations had seizures and, with the exception of 1 patient, they were not hypertensive. The mental retardation ranged from moderate to severe. Two patients also showed autistic behavior. Vervoort et al. (2002) concluded that there is a role for AGTR2 in brain development and cognitive function. Bienvenu et al. (2003) performed mutation analysis of the AGTR2 gene in 15 large families with MR linked to Xq24, a panel of 101 clinically well-characterized small families with at least 2 affected boys with MR, and 244 sporadic cases of nonspecific MR. No deleterious mutations were found in any of the patients. A novel amino acid substitution was identified as a nonpathogenic rare genetic variant. These observations suggested that AGTR2 is rarely involved in nonspecific MR but could be involved in more specific forms. | |||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||
| Angiotensin II is a potent regulator of blood pressure and of water and electrolyte balance. Whereas the type-1 receptor mediates the vasopressive and aldosterone-secreting effects of angiotensin II, the function of the type-2 receptor was unknown, although it is expressed in both adult and embryonic life. To address the question of function, Hein et al. (1995) and Ichiki et al. (1995) independently generated mice lacking the gene encoding the type-2 receptor, Agtr2. Hein et al. (1995) found that mutant mice developed normally but had an impaired drinking response to water deprivation as well as a reduction in spontaneous movements. Their baseline blood pressure was normal, but they showed an increased vasopressor response to injection of angiotensin II. These data suggested to Hein et al. (1995) that, although the angiotensin II receptor is not required for embryonic development, it plays a role in the central nervous system and cardiovascular functions that are mediated by the renin-angiotensin system. Ichiki et al. (1995) reported the unexpected finding that the targeted disruption of the mouse Agtr2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. The authors concluded that the type-2 receptor mediates a depressor effect and antagonizes the Agtr1-mediated pressor action of angiotensin II. In addition, disruption of the Agtr2 gene attenuated exploratory behavior and lowered blood pressure. Their results indicated that angiotensin II activates AGTR1 and AGTR2, which have mutually counteracting hemodynamic effects, and that AGTR2 regulates central nervous system functions, including behavior. Ichiki et al. (1995) commented on the fact that Hein et al. (1995) did not find an increase in basal blood pressure and they suggested that this could be due to differences in genetic background of the mice studied. | |||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||
| .0001 MENTAL RETARDATION, X-LINKED 88 | |||||||||||||||||||||||||||||||||||||||||||||
| AGTR2, GLY21VAL | |||||||||||||||||||||||||||||||||||||||||||||
| In a patient and his elder brother, both with profound mental retardation (300852), Vervoort et al. (2002) identified a G-to-T transition at nucleotide 62, resulting in a glycine-to-valine substitution at codon 21 (G21V), a conserved residue within the AGTR2 extracellular domain. This mutation was also found in an unrelated male with mental retardation; this patient also showed autistic behavior. The mutation was not identified in 510 X chromosomes from control males. Ylisaukko-oja et al. (2004) performed a mutation screen of the AGTR2 gene in 57 Finnish male patients with nonsyndromic mental retardation. They identified 2 missense mutations: G21V and ile53 to phe (I53F; 300034.0006). Patients with the AGTR2 sequence variants had severe/profound mental retardation, epileptic seizures, restlessness, hyperactivity, and disturbed development of speech. Erdmann et al. (2004) identified the G21V mutation in 4 individuals without mental retardation: 1 with hypertrophic cardiomyopathy, 1 with dilated cardiomyopathy, and 2 controls. In a screening of 908 individuals, the authors found a gene frequency of 0.003%, indicating that G21V is a rare polymorphism. | |||||||||||||||||||||||||||||||||||||||||||||
| .0002 MENTAL RETARDATION, X-LINKED 88 | |||||||||||||||||||||||||||||||||||||||||||||
| AGTR2, 1-BP DEL, 395T | |||||||||||||||||||||||||||||||||||||||||||||
| In 2 affected members of a large family segregating X-linked mental retardation (300852), Vervoort et al. (2002) identified a deletion of 1 thymine within a string of 8 thymines between nucleotides 395 and 402 in the AGTR2 gene. This mutation causes a frameshift. The carrier state was confirmed in 3 females in this family. One unrelated male from a group of 552 sporadic males with mental retardation screened also carried an identical frameshift mutation; this patient also showed autistic behavior. This mutation was not present in unaffected family members from the large family or in 129 X chromosomes from unaffected Caucasian males. | |||||||||||||||||||||||||||||||||||||||||||||
| .0003 MENTAL RETARDATION, X-LINKED 88 | |||||||||||||||||||||||||||||||||||||||||||||
| AGTR2, ARG324GLN [dbSNP:rs35474657] | |||||||||||||||||||||||||||||||||||||||||||||
| In 3 unrelated males with mental retardation (300852) who were negative for the FMR1 expansion, Vervoort et al. (2002) identified a G-to-A transition at nucleotide 971, resulting in an arginine-to-glutamine substitution at codon 324 (R324Q). This mutation was not observed in 510 X chromosomes from control males. | |||||||||||||||||||||||||||||||||||||||||||||
| .0004 MENTAL RETARDATION, X-LINKED 88 | |||||||||||||||||||||||||||||||||||||||||||||
| AGTR2, ILE337VAL | |||||||||||||||||||||||||||||||||||||||||||||
| In a male with mental retardation (300852), Vervoort et al. (2002) identified an A-to-G transversion at nucleotide 1009, resulting in an isoleucine-to-valine substitution at codon 337 (I337V) in the AGTR2 gene. This alters a conserved residue in the intracellular domain of AGTR2. This mutation was not identified in 510 X chromosomes from control males. | |||||||||||||||||||||||||||||||||||||||||||||
| .0005 REMOVED FROM DATABASE | |||||||||||||||||||||||||||||||||||||||||||||
| .0006 MENTAL RETARDATION, X-LINKED 88 | |||||||||||||||||||||||||||||||||||||||||||||
| AGTR2, ILE53PHE | |||||||||||||||||||||||||||||||||||||||||||||
| See 300034.0001 and Ylisaukko-oja et al. (2004). | |||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||
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