REN
protein-codingrenin, the group of Peptidase family A1
Gene summary
This gene encodes renin, an aspartic protease that is secreted by the kidneys. Renin is a part of the renin-angiotensin-aldosterone system involved in regulation of blood pressure, and electrolyte balance. This enzyme catalyzes the first step in the activation pathway of angiotensinogen by cleaving angiotensinogen to form angiotensin I, which is then converted to angiotensin II by angiotensin I converting enzyme. This cascade can result in aldosterone release, narrowing of blood vessels, and increase in blood pressure as angiotension II is a vasoconstrictive peptide. Transcript variants that encode different protein isoforms and that arise from alternative splicing and the use of alternative promoters have been described, but their full-length nature has not been determined. Mutations in this gene have been shown to cause hyperuricemic nephropathy familial juvenile 2, familial hyperproreninemia, and renal tubular dysgenesis. [provided by RefSeq, May 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~35.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013128
Submitter: ClinGen
REN was FIRST reported in relation to autosomal dominant tubulointerstitial kidney (ADTKD; OMIM: 613092) in 2009 (Zivna et al, PMID: 19664745). ADTKD-REN is characterized by a family history of chronic kidney disease, childhood anemia (if the mutation is located in the signal peptide or prosegment of renin), hyperuricemia (in 60% of cases), mild hyperkalemia, bland urinary sediment and slowly progressive chronic kidney disease, leading to end-stage kidney disease (ESKD) at between 30 – 80 years of age (PMIDs: 32750457, 19664745, 21084044, 21903317, 28701203, 31406136, 31586593). The REN gene is associated with two disease entities by different pattern of inheritance and molecular mechanisms as well as different clinical findings including: (1) Autosomal dominant tubulointerstitial kidney disease (ADTKD-REN; OMIM: 613092) and (2) Renal tubular dysgenesis (RTD; OMIM: 267430). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, these two disease entities have been curated separately. Variants in REN have been reported in at least 120 individuals (from more than 30 families) and segregated with the disease (PMIDs: 19664745, 32750457, 21084044, 21903317, 28701203, 31406136, 31586593). At least 15 unique variants (including in-frame deletion and missense variants) have been reported. Renin is synthesized as pre-pro-renin consisting of a signal peptide (pre), prosegment (pro) and mature part of renin. More than 60% of cases are caused by mutations in the signal peptide, 25% of mutations are in the prosegment and 15% are in the mature part renin. The mechanism of the disease depends on the mutated domain. Mutations in the signal peptide result in synthesis of a preprorenin that is not processed and is aberrantly located in the cytoplasm. Mutations in the prosegment introduce structural changes affecting protein biosynthesis, folding, and transport along the secretory pathway. Mutations in mature renin lead to retention of the mutated protein in the endoplasmic reticulum. All of these molecular mechanisms result in ER stress activation and cellular toxicity to renin-producing cells, leading to apoptosis, clinical renin deficiency and chronic kidney disease. ADTKD-REN patients have hyporeninemic hypoaldosteronism, which can be treated with administration of the synthetic aldosterone analog fludrocortisone (PMIDs: 21084044, 21473025). This gene-disease association is supported by immunohistochemical studies of renin in patient kidney biopsies, determination of plasma renin levels, experimental cellular models (PMIDs: 19664745, 32750457) and a zebrafish model (PMID: 31406136). In summary, there is DEFINITIVE evidence to support the relationship between REN and autosomal dominant tubulointerstitial kidney disease (ADTKD-REN). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP Working Group on 10/28/2020 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: ClinGen
REN was FIRST reported in relation to autosomal recessive renal tubular dysgenesis (RTD; OMIM: 267430) in 2005 (Gribouval et al, PMID: 16116425). RTD is characterized by prenatal development with hypoperfusion during fetal development leading to abnormal kidney development, persistent anuria, persistent oligohydramnios that leads to the Potter sequence (clubbed feet, pulmonary hypoplasia and cranial anomalies), skull ossification defects and perinatal death. The histopathological hallmark of the disease is absence or poor development of proximal tubules and glomeruli. Approximately 20% of RTD cases are caused by either homozygous or compound heterozygous mutations in REN. Other known cases of RTD are associated with biallelic mutations in genes encoding other components of the renin-angiotensin system (RAS, e.g. angiotensin and angiotensin converting enzyme). The REN gene is associated with two disease entities by different inheritance patterns and molecular mechanisms, as well as different clinical findings including: (1) renal tubular dysgenesis (RTD-REN; OMIM: 267430) and (2) autosomal dominant tubulointerstitial kidney disease (ADTKD-REN; OMIM: 613092). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, these two disease entities have been curated separately. Variants in the REN gene have been reported in at least 20 individuals (PMIDs: 16116425, 22095942, 17443344, 27994858). Homozygous or compound heterozygous variants in this gene segregated with the disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is loss of function. Biallelic nonsense, frameshift or splice site mutations in REN result in undetectable expression of renin RNA or protein in kidney sections (PMID: 16116425; PMID: 22095942). Conversely, biallelic non-truncating mutations or missense mutations of the active site altered renin trafficking and sorting resulting in marked kidney accumulation of defective renin with a dramatically low level of plasma active renin (PMID: 22095942). Aberrant function of renin (as well as other RAS components) affects nephron development and causes the RTD phenotype. This gene-disease association is supported by immunohistochemical studies of renin in kidney biopsies of affected individuals, determination of active renin in plasma, experimental cellular models and a knockout rat model (PMID: 21036942; PMID: 21242461). In summary, there is DEFINITIVE evidence to support the relationship between REN and autosomal recessive renal tubular dysgenesis (RTD). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on 10/28/2020 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013128
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013128
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013128
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013128
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Renal
Intervention: Pharmacogenomic; Renal
Rationale: Surveillance for hematologic (anemia) and renal (hyperuricemia, decreased renal function) disease may be beneficial to allow early medical management; Treatment of low plasma renin activity/low plasma concentration of aldosterone (eg, through management of sodium intake), as well as medical management of hyperkalemia (eg, with fludrocortisones, potassium restriction) may be beneficial, and may be indicated prior to the development of severe chronic kidney disease, though kidney transplantation may be necessary; Treatment of anemia (with erythropoietin) may be effective; Preventive treatment of hyperuricemia (eg, with allopurinol) and medical treatment of gout (eg, with prednisone, colchicines) may be effective; Certain agents should be avoided, including NSAIDS, ACE-inhibitors, dehydration, and specific dietary practices that can exacerbate gout
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to REN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000537.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 42 | 1 | 48 | ||
| missense | 4 | 5 | 124 | 13 | 1 | 147 |
| nonsense | 3 | 3 | 6 | |||
| start loss | 0 | |||||
| frameshift | 2 | 4 | 6 | |||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 10 | 15 | 129 | 55 | 2 | 211 |
Highest pathogenic variant AF is 0.000030360146
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000528.1 | 10 | MANE Select | |
| Ensembl | ENSP00000272190.8 | 10 | MANE Select | |
| Ensembl | ENSP00000490307.1 | 9 | Standard | |
| Ensembl | ENSP00000490307.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics
- Renin-angiotensin system - Homo sapiens (human)
- Renin secretion - Homo sapiens (human)
- ACE Inhibitor Pathway, Pharmacodynamics
- Temocapril Action Pathway
Biological Process
- kidney development
- mesonephros development
- angiotensin maturation
- renin-angiotensin regulation of aldosterone production
- proteolysis
Molecular Function
- aspartic-type endopeptidase activity
- signaling receptor binding
- insulin-like growth factor receptor binding
- protein binding
- peptidase activity
Cellular Component
- extracellular region
- extracellular space
- cytoplasm
- plasma membrane
- apical part of cell
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000272190
- Coding exons
- 10
- Length
- 11522
- Individuals with no LoFs
- 125684
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 64
- Defined
- 125748
- p
- 0.000255
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.797 | 199 | 233 | 0.853 | 0.0000144 | 2643 |
| Missense (PolyPhen) | 47 | 75.491 | 0.62259 | 893 | ||
| Synonymous | -0.889 | 108 | 96.9 | 1.11 | 0.00000683 | 810 |
| Loss of Function | 1.71 | 14 | 22.8 | 0.614 | 0.00000135 | 242 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00071 | 0.00071 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.00034 | 0.00033 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.;
- Disease
- DISEASE: Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial juvenile hyperuricemic nephropathy 2 (HNFJ2) [MIM:613092]: A renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia. {ECO:0000269|PubMed:19664745}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.891
Intolerance Scores
- LoFtool
- 0.728
- RVIS EVS
- -0.4
- RVIS percentile EVS
- 26.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.752
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |