HGNC Approved Gene Symbol: REN
SNOMEDCT: 702397002;
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:204,154,819-204,166,337 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | [Hyperproreninemia] | 3 | ||
| Renal tubular dysgenesis | 267430 | Autosomal recessive | 3 | |
| Tubulointerstitial kidney disease, autosomal dominant, 4 | 613092 | Autosomal dominant | 3 |
Released by the juxtaglomerular cells of the kidney, renin (EC 3.4.23.15) catalyzes the first step in the activation pathway of angiotensinogen, a cascade that can result in aldosterone release, vasoconstriction, and increase in blood pressure. Renin cleaves angiotensinogen to form angiotensin I (106150), which is converted to angiotensin II by angiotensin I-converting enzyme (106180), an important regulator of blood pressure and electrolyte balance. Renin occurs in organs other than the kidney, e.g., in the brain, where it is implicated in the regulation of numerous activities.
Imai et al. (1983) sequenced full-length cDNA clones prepared from RNA extracted from a surgically removed ischemic kidney in which the renin content was markedly increased due to renal artery stenosis. The primary structure of renin precursor was deduced from its cDNA sequence: it consists of 406 amino acids with a pre and a pro segment carrying 20 and 46 amino acids, respectively. A high degree of homology was found with mouse renin. Close similarity was also observed in the primary structures of renin and aspartyl proteinases.
By transfection experiments with the human renin gene in fibroblast cells and pituitary tumor cells, Pratt et al. (1988) demonstrated that human renin may be secreted by at least 2 cellular pathways: a constitutive pathway for the secretion of prorenin and a regulated pathway for the secretion of mature renin.
Nguyen et al. (2002) identified ATP6AP2 (300556) as the gene encoding renin receptor. Using coimmunoprecipitation experiments, they confirmed that renin receptor bound renin and prorenin. Binding of renin to the receptor induced a 4-fold increase in conversion of angiotensinogen to angiotensin I over that shown by soluble renin. In addition, renin stimulation resulted in phosphorylation of serine and tyrosine residues of the receptor, which was associated with ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) activation.
Yokota et al. (2007) found that serum prorenin levels in preterm infants with retinopathy of prematurity (ROP) were significantly higher than in those without ROP: mean prorenin concentrations of 2,326 versus 1,1165 microgram/ml from 26 to 30 weeks, 1,760 versus 957 microgram/ml from 31 to 36 weeks, and 576 versus 386 micrograms/ml from 36 to 40 weeks, respectively. Yokota et al. (2007) suggested that prorenin levels in preterm infants could predict which infants would develop ROP.
According to Hobart et al. (1984), the renin gene spans 12 kb of DNA and contains 8 introns. The structure of the renin gene is similar to that of pepsinogen (169700), a closely related aspartyl protease. Thus, renin and pepsinogen probably have a common evolutionary origin.
A renin probe was used by Naylor et al. (1984) to map human REN by the analysis of hybrid cell DNAs. Assignment was made to human 1p21-qter. Middleton-Price et al. (1987) assigned the REN gene to 1q32-qter by in situ hybridization, Southern analysis of somatic cell hybrids, and deletion mapping. This localization is consistent with the prediction from homology with the mouse. In studies of DNA from an infant with deletion of 1q32.3-q42.3, Youssoufian et al. (1988) excluded this area as the site of REN. McGill et al. (1987) mapped the renin gene to 1q25-q32 by in situ hybridization. By hybridization to somatic cell hybrid DNAs, Griffiths et al. (1987) assigned the REN gene to 1q12-qter. They were unable to find evidence of linkage to Charcot-Marie-Tooth disease (118200), which was not unexpected since REN may be located as far distal as 1q32. By in situ hybridization, Nakai et al. (1988) localized the REN gene to 1q41-q42, probably on 1q42, which is inconsistent with earlier findings. In a linkage map of chromosome 1 prepared by Rouleau et al. (1990), it was concluded that REN lies about 24 cM distal to AT3. By isotopic in situ hybridization studies in a patient with a translocation t(1;4)(q42;p16), Qin et al. (1993) demonstrated that hybridization signals were confined to the 1q32 band, with radioactivity in the 1q42 region being similar to the low levels found along all other chromosomes.
All mice have a kidney-type renin gene, Ren1, which is located on mouse chromosome 1 (Chirgwin et al., 1984). In some mouse strains, the male submaxillary gland secretes large amounts of renin. These mice have a second renin locus (Ren2), also on chromosome 1. The rat also has 2 Ren genes, which are in close proximity, being separated by approximately 20 kb (Abel and Gross, 1988). This situation is similar to that for insulin (176730), for which there are likewise 2 loci in rodents. Chirgwin et al. (1984) suggested that those that have the second renin locus have had a tandem duplication of the renal-type renin locus. By study of a panel of rat/mouse somatic cell hybrids, Pravenec et al. (1991) found that in the rat the renin gene is located on chromosome 13 in a conserved synteny group located on chromosome 1 in man and mouse.
Morris and Griffiths (1988) could find no relationship between primary hypertension and a HindIII RFLP in the renin gene. The frequency of alleles for the HindIII polymorphism in hypertensives did not differ from that in controls, and there was no significant difference in renin activity in plasma for hypertensive patients of each genotype, nor in their pre- or post-treatment blood pressures. Using 4 RFLPs of the REN locus, Naftilan et al. (1989) excluded absolute linkage by observing obligate recombinants among 9 relatives with hypertension in a large Utah pedigree with a high incidence of hypertension. Masharani and Frossard (1988) described a RFLP at the REN locus. Using the sib-pair method of linkage analysis, Jeunemaitre et al. (1992) could demonstrate no role for the renin gene in the pathogenesis of essential hypertension.
Frossard et al. (1986) described a dimorphic BglI site in the first intron of the REN gene. Frossard et al. (1999) found a statistically significant association between alleles on which the BglI site was present and the clinical diagnosis of essential hypertension in 2 independent populations: one from the United Emirates, a genetically homogeneous ethnic population with no history of smoking or alcohol consumption, and to a lesser extent, in a U. S. Caucasian group that was studied for hypercholesterolemia.
Gribouval et al. (2005) studied 11 individuals with renal tubular dysgenesis (267430) belonging to 9 families and found that they had homozygous or compound heterozygous mutations in the genes encoding renin (REN), angiotensinogen (AGT; 106150), angiotensin-converting enzyme (ACE; 106180), or angiotensin II receptor type 1 (AGTR1; 106165). They proposed that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This appeared to be the first identification of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.
Autosomal Dominant Tubulointerstitial Kidney Disease 4
Zivna et al. (2009) analyzed the candidate gene renin in 3 families segregating autosomal dominant tubulointerstitial kidney disease-4 (ADTKD4; 613092), 1 of which was originally reported as family BE1 by Stiburkova et al. (2003), and identified a heterozygous 3-bp deletion in 2 of the families (179820.0004) and a heterozygous missense mutation in the third family (179820.0005). The mutations were not found in unaffected family members or controls.
Rapp et al. (1989) found that Dahl rats sensitive to hypertension with salt administration had a different RFLP in the renin gene than did Dahl rats resistant to hypertension. They found, furthermore, that when the sensitive and resistant rats were crossed, the renin RFLP cosegregated with blood pressure in the F2 generation. One dose of the 'sensitive' renin allele was associated with an increment of blood pressure approximately 10 mm Hg, and 2 doses increased blood pressure approximately 20 mm Hg. Rapp et al. (1989) concluded that in the rat the renin gene is, or is closely linked to, one of the genes regulating blood pressure.
Mullins et al. (1990) demonstrated that introduction of the mouse Ren2 renin gene into the genome of the rat induced severe hypertension despite the fact that the transgenic animals did not overexpress active renin in the kidney and had low levels of active renin in their plasma. The transgenic hypertensive rat model TGR(mREN2)27 generated by Mullins et al. (1990) is characterized by fulminant hypertension, low plasma active renin, suppressed kidney renin, high plasma inactive renin, and high extrarenal transgene expression, most prominently in the adrenal cortex. Additionally, it exhibits significantly enhanced excretion of corticosteroids. In these rats, Peters et al. (1993) demonstrated that part of the plasma renin and most of the adrenal renin are transgene determined and that the adrenal renin is strongly activated. Kurtz (1993) pointed out that 'To the extent that transgenic models reveal novel mechanisms of increased blood pressure, they may provide important new perspectives for investigating the genetic basis of spontaneous forms of hypertension. However, the development of gene targeting methods that enable the creation of animal models with selective nucleotide substitutions will ultimately be required to determine the precise role of specific candidate genes in the pathogenesis of essential hypertension.'
Pravenec et al. (1991) studied a large set of recombinant inbred (RI) strains derived from spontaneously hypertensive rats (SHR) and normotensive brown-Norway (BN) rats. They found that the median blood pressure of the RI strains that inherited the renin allele of the SHR to be greater than that of the RI strains that inherited the renin allele of the normotensive BN rat. They interpreted these findings as indicating that sequence variation in the renin gene or in genes linked to the renin locus have an effect on blood pressure in the rat.
Caron et al. (2004) studied one of the mouse models valuable for investigating hypertrophic responses to cardiac stress. This model was caused by a well-defined single copy transgene involving the renin gene that genetically clamps plasma renin and thence angiotensin II at high levels. All of the transgenic males developed concentric cardiac hypertrophy with fibrosis but without dilatation. More than half died suddenly at the age of 6 to 8 months. Telemetry showed disturbances in diurnal rhythms a few days before death and, later, electrocardiographic disturbances comparable to those in humans with congestive heart failure. Comparisons were made of the expression of 7 hypertrophy-related genes in this and 2 categorically different models: lack of atrial natriuretic peptide receptor A (NPR1; 108960) and overexpression of calsequestrin (CASQ2; 114251). Statistical analyses showed that ventricular expressions of the genes encoding atrial natriuretic peptide, beta myosin heavy chain, medium chain acyl-CoA dehydrogenase, and adrenomedullin (103275) correlated equally well with the degree of hypertrophy, although their ranges of expression were, respectively, 50-, 30-, and 10-, and 3-fold.
During an epidemiologic survey of a Dutch population, van Hooft et al. (1991) found a family in which plasma trypsin-activated prorenin was elevated in the 58-year-old father, his son, and 1 of his sisters. All family members were normotensive and had normal plasma renin activities. By exon sequencing of the renin gene of the proband and of his son after PCR amplification, Villard et al. (1994) identified a point mutation in the last exon of the gene, exon 10. Mutation occurred at a position corresponding to codon 387 of the preprorenin cDNA. A C-to-T transition introduced a premature stop codon (TGA) in the renin gene sequence in place of the normal CGA (arg) at codon 387. The mutated allele should direct the synthesis of a truncated form of renin, with 20 amino acids deleted from the carboxyl terminus.
In a consanguineous family of North African extraction, Gribouval et al. (2005) found a 145C-T transition in exon 2 of the REN gene associated with renal tubular dysgenesis (267430). The mutation was predicted to cause an arg49-to-stop (R49X) protein change.
In a consanguineous family of Tunisian origin, Gribouval et al. (2005) found that renal tubular dysgenesis (267430) was associated with a homozygous arg230-to-lys (R230K) mutation in renin. The amino acid substitution was caused by a 689G-A transition in exon 5.
In the proband from a 4-generation Belgian family segregating autosomal dominant tubulointerstitial kidney disease-4 (ADTKD4; 613092) originally reported by Stiburkova et al. (2003) as family BE1, Zivna et al. (2009) identified heterozygosity for a 3-bp deletion in exon 1 of the REN gene, predicted to result in the deletion of leu16 (L16del). The deletion was present in all affected individuals and was not found in unaffected family members or in 385 unrelated Caucasian controls. The identical mutation was present on a distinct haplotype in another family with hyperuricemic nephropathy (family B). Transfection and in vitro studies showed that L16del affected ER translocation and processing of nascent prorenin, resulting in reduction of renin biosynthesis and secretion. Cells stably expressing the L16del protein showed activated ER stress, unfolded protein response,and reduced growth rate.
In affected members of a family of Portuguese origin (family C) with autosomal dominant tubulointerstitial kidney disease-4 (ADTKD4; 613092), Zivna et al. (2009) identified a heterozygous c.47T-G transversion in exon 1 of the renin gene, predicted to result in a leu16-to-arg (L16R) substitution. Transfection and in vitro studies showed that L16R affected ER translocation and processing of nascent prorenin, abolishing renin biosynthesis and secretion. The mutation was not found in unaffected family members or in 185 Caucasian controls and 50 Portuguese controls.
In an Italian girl, born of consanguineous parents, with renal tubular dysgenesis (267430), Gribouval et al. (2012) identified a homozygous c.127C-T transition in exon 2 of the REN gene, resulting in an arg43-to-ter (R43X) substitution. The girl died on the fourth day of life.
In a girl, born of consanguineous Algerian parents, with renal tubular dysgenesis (267430), Zingg-Schenk et al. (2008) identified a homozygous 404C-A transversion in exon 4 of the REN gene, resulting in a ser135-to-tyr (S135Y) substitution. The patient survived the neonatal period with peritoneal dialysis and underwent renal transplant at age 4 years. She showed normal psychomotor development at age 10 years.
Michaud et al. (2011) identified a homozygous S135Y mutation in a Moroccan infant with renal tubular dysgenesis who died in the first hour of life. The S135Y substitution corresponds to S69Y in the mature protein, and is located at a highly conserved residue close to the beginning of a lengthy beta-hairpin structure called the 'flap,' which is required for proper enzymatic function. In vitro functional expression studies suggested that the mutation resulted in abnormal secretion and intracellular protein degradation, likely due to incorrect protein folding. Secretion of some of the mutant protein could be partially restored by decreasing temperature and by proteasomal inhibition.
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