CAVIN1
protein-codingcaveolae associated protein 1, the group of Cavins
Gene summary
This gene encodes a protein that enables the dissociation of paused ternary polymerase I transcription complexes from the 3' end of pre-rRNA transcripts. This protein regulates rRNA transcription by promoting the dissociation of transcription complexes and the reinitiation of polymerase I on nascent rRNA transcripts. This protein also localizes to caveolae at the plasma membrane and is thought to play a critical role in the formation of caveolae and the stabilization of caveolins. This protein translocates from caveolae to the cytoplasm after insulin stimulation. Caveolae contain truncated forms of this protein and may be the site of phosphorylation-dependent proteolysis. This protein is also thought to modify lipid metabolism and insulin-regulated gene expression. Mutations in this gene result in a disorder characterized by generalized lipodystrophy and muscular dystrophy. [provided by RefSeq, Nov 2009]
- PTRF
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0006573
Submitter: ClinGen
*CAVIN1* (previously known as *PTRF*) was first reported in relation to autosomal recessive inherited congenital generalized lipodystrophy type 4 (CGL4, OMIM:613327) in 2009 (Hayashi et al., PMID: 19726876), with variants in affected individuals being in homozygous (n= 4) or compound heterozygous (n=1) status. Typically, CGL4 patients are characterized by some unique clinical features (PMIDs: 12116229), including congenital myopathy, cardiac arrythmias, congenital pyloric stenosis, gastrointestinal dysmotility, and skeletal abnormalities compared with other CGL subtypes. Elevated serum creatine kinase levels, and percussion-induced muscle mounding are also typical of CGL4 (PMIDs: 19726876, 20300641, 20684003, 20684003, 20638880, 24024685, 23489663, 25721873, 25994244, 27167729, 27144933, 27144934, 30476128, 32467771, 35405042, 35989241, 36946378, 38234231). At least 21 null mutations, including 8 nonsense and 13 frameshift variants, have been reported in at least 46 patients (reviewed in Akinci et al. PMID: 38234231) in several publications. Variants in this gene segregated with disease in at least 3 family members (PMIDs: 38234231, 20300641). For the purpose of this curation, 2 variants from Hayashi et al (PMID:19726876), 2 from Rajab et al (PMID: 20300641) and 8 from Akinci et al (PMID: 38234231) are included. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Initial mechanistic studies suggest that many of the mutations result in the absence of detectable CAVIN/PTRF protein, with subsequent perturbation of caveolin expression and localization leading to disrupted and/or reduced formation of caveolae (PMID: 19726876, 20300641, 27144934). This gene-disease relationship is also supported by animal models (PMIDs: 28289716,18840361) showing that Cavin1/PTRF is essential for caveolae formation in vivo in all tissues. *Cavin1*-knockout mice lack morphologically detectable caveolae in several cell types, including intestinal smooth muscle and skeletal muscle. As a characteristic of the lipodystrophic phenotype, these mice exhibit significantly reduced adipose tissue mass, elevated circulating triglyceride levels, glucose intolerance, and hyperinsulinemia (PMID: 18840361). *Cavin1* null mice also show reduced exercise capacity and muscle hypertrophy with increased fiber size and mass; however, these muscle tissues are fibrotic and exhibit impaired regeneration (PMID: 28289716). Experimental evidence: 6 points. Total evidence: 18 points. In summary, there is definitive evidence supporting the relationship between *CAVIN1* (previously known as *PTRF*) and autosomal recessive inherited congenital generalized lipodystrophy type 4. Gene-Disease Validity Standard Operating Procedures (SOP) - SOP11.
Inheritance Pattern: AR
Disease ID:MONDO:0013225
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013225
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal
Intervention: Cardiovascular
Rationale: Among other manifestations, individuals may demonstrate cardiac arrhythmias, and appropriate surveillance and management may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CAVIN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012232.6. 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 | 24 | 1 | 30 | ||
| missense | 68 | 7 | 75 | |||
| nonsense | 1 | 3 | 4 | |||
| start loss | 0 | |||||
| frameshift | 8 | 3 | 11 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 10 | 6 | 74 | 31 | 1 | 122 |
Highest pathogenic variant AF is 0.000017379947
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036364.2 | 2 | MANE Select | |
| Ensembl | ENSP00000349541.4 | 2 | MANE Select | |
| Ensembl | ENSP00000540295.1 | 2 | Standard | |
| Ensembl | ENSP00000614781.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cavin1a | Danio rerio | Structure: skeletal muscle cell Quality: convolute abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Gene expression (Transcription)
- RNA Polymerase I Transcription Termination
- RNA Polymerase I Transcription
- EGFR1
Biological Process
- transcription initiation from RNA polymerase I promoter
- termination of RNA polymerase I transcription
- rRNA transcription
- positive regulation of cell motility
Molecular Function
- RNA binding
- protein binding
- rRNA primary transcript binding
- identical protein binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- mitochondrion
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000357037
- Coding exons
- 2
- Length
- 21066
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 17
- Defined
- 125747
- p
- 0.0000676
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.38 | 195 | 257 | 0.759 | 0.0000196 | 2482 |
| Missense (PolyPhen) | 116 | 153.97 | 0.75337 | 1540 | ||
| Synonymous | 1.08 | 108 | 123 | 0.876 | 0.00000997 | 806 |
| Loss of Function | 1.40 | 5 | 9.71 | 0.515 | 4.26e-7 | 137 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000054 | 0.000053 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an important role in caveolae formation and organization. Essential for the formation of caveolae in all tissues (PubMed:18056712, PubMed:18191225, PubMed:19726876). Core component of the CAVIN complex which is essential for recruitment of the complex to the caveolae in presence of calveolin-1 (CAV1). Essential for normal oligomerization of CAV1. Promotes ribosomal transcriptional activity in response to metabolic challenges in the adipocytes and plays an important role in the formation of the ribosomal transcriptional loop. Dissociates transcription complexes paused by DNA-bound TTF1, thereby releasing both RNA polymerase I and pre-RNA from the template (By similarity). {ECO:0000250|UniProtKB:O54724, ECO:0000269|PubMed:18056712, ECO:0000269|PubMed:18191225, ECO:0000269|PubMed:19726876}.;
- Disease
- DISEASE: Congenital generalized lipodystrophy 4 (CGL4) [MIM:613327]: A disorder characterized by the association of congenital generalized lipodystrophy with muscular dystrophy and cardiac anomalies. Congenital generalized lipodystrophy is characterized by a near complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. {ECO:0000269|PubMed:19726876, ECO:0000269|PubMed:20684003}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.265
Intolerance Scores
- RVIS EVS
- -0.03
- RVIS percentile EVS
- 51.66
Essentials
- Essential (gene trap)
- N