Alternative titles; symbols
HGNC Approved Gene Symbol: CAV1
Cytogenetic location: 7q31.2 Genomic coordinates (GRCh38): 7:116,525,009-116,561,185 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.2 | Lipodystrophy, congenital generalized, type 3 | 612526 | Autosomal recessive | 3 |
| Lipodystrophy, familial partial, type 7 | 606721 | Autosomal dominant | 3 | |
| Pulmonary hypertension, primary, 3 | 615343 | Autosomal dominant | 3 |
The CAV1 gene encodes caveolin-1, an integral membrane protein abundant in the endothelium and other cells in the lung. It is the main component of the flask-like invaginations of the plasma membrane known as caveolae (summary by Austin et al., 2012).
Glenney (1992) cloned and sequenced a human cDNA encoding caveolin from lung. He observed a striking sequence similarity to the vesicle transport protein VIP21 (see Kurzchalia et al., 1992). Scherer et al. (1996) reviewed the literature on caveolin. Structurally, caveolin can be divided into 3 distinct regions: a hydrophilic cytosolic N-terminal domain, a membrane-spanning region, and a hydrophilic C-terminal domain. The C-terminal domain undergoes palmitoylation (S-acylation) on 3 cysteine residues, suggesting that both the membrane-spanning region and the C-terminal domain of caveolin are associated with the membrane. They stated that caveolin may function as a scaffolding protein for organizing and concentrating certain caveolin-interacting molecules within caveolae membranes.
The CAV1 gene is translated as a full-length protein of 178 amino acids in its alpha isoform. Using immunohistochemical studies, Austin et al. (2012) found that CAV1 is expressed primarily on the endothelial cell surface of pulmonary arteries, with some staining in the cytoplasm of endothelial cells.
Caveolae ('little caves') are plasma membrane specializations present in most cell types. Scherer et al. (1996) noted that they are most conspicuous in adipocytes where they represent up to 20% of the total plasma membrane surface area. Cytoplasmically oriented signal molecules are concentrated within these structures, including heterotrimeric guanine nucleotide-binding proteins (G proteins; see 600239), Src-like kinases (see 124095), protein kinase C-alpha (176960), and Ras-related GTPases (see 139150). The caveolar localization of signaling molecules may provide a compartmental basis for integrating certain transmembrane signaling events.
Engelman et al. (1998) reviewed the molecular genetics of the caveolin gene family. They compared the genomic organization of the CAV1, CAV2 (601048), and CAV3 (601253) genes. The CAV1 gene contains 3 exons, while the human CAV2 gene contains 2 exons. The boundary of the last exon of CAV1 and CAV2 are analogous, suggesting that they arose through gene duplication. The muscle-specific CAV3 is conserved, both at the level of sequence and at the level of chromosomal context, between mouse and man. Caveolins with sequence similarities to human CAV1 and CAV2 exist in C. elegans.
Ghorpade et al. (2018) showed that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase-4 (DPP4; 102720), which acts with plasma factor Xa (see 613872) to inflame adipose tissue macrophages. Silencing expression of DPP4 in hepatocytes suppressed inflammation of visceral adipose tissue and insulin resistance; however, a similar effect was not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance were also suppressed by silencing expression of caveolin-1 or PAR2 (600933) in adipose tissue macrophages; these proteins mediate the actions of DPP4 and factor Xa, respectively. Ghorpade et al. (2018) concluded that hepatocyte DPP4 promotes visceral adipose tissue inflammation and insulin resistance in obesity, and that targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.
Scherer et al. (1995) showed that murine Cav encodes 1 mRNA but 2 caveolin isoforms that differ by approximately 3 kD. They termed the 2 isoforms alpha- and beta-caveolin. Alpha-caveolin contains residues 1-178; methionine-32 acts as an internal translation initiation site to form the shorter beta-caveolin. The authors stated that both caveolin isoforms are targeted to caveolae, form homooligomers, and interact with G proteins. However, alpha- and beta-caveolin assume a distinct but overlapping subcellular distribution in intact cells and only beta-caveolin is phosphorylated on serine residues in vivo. These findings suggested to the authors that coexpression of alpha- and beta-caveolin within a single cell may be used to generate at least 2 distinct subpopulations of caveolae that may be differentially regulated by a specific caveolin-associated serine kinase.
Scherer et al. (1996) found that residues 82-101 of murine caveolin-1 functionally suppressed the basal GTPase activity of purified heterotrimeric G proteins, whereas the corresponding region of caveolin-2 (which is 30% identical) had a stimulatory effect.
Wary et al. (1998) showed that caveolin-1 functions as a membrane adaptor to link the integrin alpha subunit (see 603963) to the tyrosine kinase FYN (137025). Upon integrin ligation, FYN is activated and binds, via its SH3 domain, to SHC (600560). SHC is subsequently phosphorylated at tyrosine-317 and recruits GRB2 (108355). This sequence of events is necessary to couple integrins to the Ras-ERK pathway and promote cell cycle progression.
In addition to the role of mutations in CAV3 in limb-girdle muscular dystrophy, Engelman et al. (1998) reviewed the cell culture and biochemical findings suggesting that heritable differences in the interaction between caveolins and their partners may lead to other conditions as well. They reviewed the evidence that CAV1 is a tumor suppressor gene and a negative regulator of the Ras-p42/44 MAP kinase cascade. Loss of heterozygosity analysis implicates 7q31.1 in the pathogenesis of multiple types of cancer, including breast, ovarian, prostate, and colorectal carcinoma, as well as uterine sarcomas and leiomyomas. Yang et al. (1998) found elevated caveolin-1 levels associated with lymph node metastasis in prostate cancer (176807), raising the possibility that CAV1 may also act as an oncogene. Because the closest known gene to CAV1 is the MET protooncogene (164860), however, this finding may simply reflect coamplification of CAV1 along with MET. MET was first identified and cloned as a metastasis-associated gene (Giordano et al., 1989).
Tahir et al. (2001) demonstrated that caveolin-1 expression is significantly increased in primary and metastatic human prostate cancer after androgen ablation therapy. They also showed that caveolin-1 is secreted by androgen-insensitive prostate cancer cells, and that this secretion is regulated by steroid hormones. Their overall results established caveolin-1 as an autocrine/paracrine factor that is associated with androgen-insensitive prostate cancer. They suggested that caveolin-1 might be a therapeutic target in the case of prostate cancer.
Engelman et al. (1998) reviewed the role of caveolae and caveolins in insulin signaling and therefore their possible role in diabetes. They also reviewed the role of caveolae and caveolins in the processing of A-beta amyloid peptide (APP; 104760) in brain and therefore their possible role in Alzheimer disease.
Engelman et al. (1998) noted that caveolins share with other scaffolding factors the ability to bind multiple components of a signaling pathway. The existence of such factors clearly affords the cell tighter control of the activation and repression of signaling than would be possible if all players diffused freely throughout the cytoplasm. Scaffolds also allow for integration of signal-transduction pathways into distinct modules, so that they reduce the likelihood of indiscriminate cross-talk among distinct pathways. A novel class of disease mutations may come to light in which the root cause of the disorder is the failure of a regulatory protein to interact properly with scaffolding factors.
From studies in cultured bovine aortic endothelial cells, Feron et al. (1999) derived data that established a new mechanism for the cholesterol-induced impairment of nitric oxide production through the modulation of caveolin abundance in endothelial cells. They suggested that this mechanism may participate in the pathogenesis of endothelial dysfunction and the proatherogenic effects of hypercholesterolemia.
PrPc, the cellular, nonpathogenic isoform of prion protein (PrP; 176640), is a ubiquitous glycoprotein expressed strongly in neurons. Mouillet-Richard et al. (2000) used the murine 1C11 neuronal differentiation model to search for PrPc-dependent signal transduction through antibody-mediated crosslinking. They observed caveolin-1-dependent coupling of PrPc to the tyrosine kinase FYN. Mouillet-Richard et al. (2000) suggested that clathrin (see 118960) might also contribute to this coupling.
Ohnuma et al. (2004) demonstrated that CD26 (102720) binds to the scaffolding domain of CAV1 on antigen-presenting cells. The binding takes place by means of residues 201 to 226 of CD26, along with the serine catalytic site at position 630. On monocytes expressing tetanus toxoid (TT) antigens, the CD26-CAV1 interaction led to CAV1 phosphorylation, NFKB (see 164011) activation, and upregulation of CD86 (601020). Reduction of CAV1 expression inhibited CD26-mediated upregulation of CD86 and abrogated CD26-mediated enhancement of TT-induced T-cell proliferation. Ohnuma et al. (2004) concluded that the CD26-CAV1 interaction plays a role in CD86 upregulation on antigen-loaded monocytes and the subsequent engagement of CD86 with CD28 on T cells, leading to antigen-specific T-cell activation.
Hovanessian et al. (2004) identified a conserved CAV1-binding motif in the human immunodeficiency virus (HIV) transmembrane envelope glycoprotein gp41. Immunoprecipitation analysis showed that gp41 and synthetic peptides containing the CAV1-binding motif bound CAV1. Rabbit antibodies to the synthetic peptides inhibited T-lymphocyte infection by HIV primary isolates. Hovanessian et al. (2004) noted that antibodies to the peptides are rare in HIV-infected individuals and proposed that the peptides may be useful as a universal B-cell epitope vaccine or as immunotherapeutic agents.
Pelkmans and Zerial (2005) explored the role of kinases in caveolae dynamics. They discovered that caveolae operate using principles different from classical membrane trafficking. First, each caveolar coat contains a set number (1 'quantum') of caveolin-1 molecules. Second, caveolae are either stored as in stationary multicaveolar structures at the plasma membrane, or undergo continuous cycles of fission and fusion with the plasma membrane in a small volume beneath the surface, without disassembling the caveolar coat. Third, a switch mechanism shifts caveolae from this localized cycle to long-range cytoplasmic transport. Pelkmans and Zerial (2005) identified 6 kinases that regulate different steps of the caveolar cycle. Their observations revealed new principles in caveolae trafficking and suggested that the dynamic properties of caveolae and their transport competence are regulated by different kinases operating at several levels.
Yamamoto et al. (2006) presented evidence that LRP6 (603507) is internalized with caveolin in human cell lines and that the components of this endocytic pathway are required for WNT3A (606359)-induced internalization of LRP6 and for accumulation of beta-catenin (CTNNB1; 116806). The data suggested that WNT3A triggers interaction of LRP6 with caveolin and promotes recruitment of AXIN (AXIN1; 603816) to LRP6 phosphorylated by GSK3B (605004) and that caveolin thereby inhibits binding of beta-catenin to AXIN. Yamamoto et al. (2006) concluded that caveolin plays critical roles in inducing internalization of LRP6 and activating the WNT/beta-catenin pathway.
Using microarray, immunohistochemical, RT-PCR, and immunoblot analyses, Wang et al. (2006) found that expression of CAV1 was significantly reduced in lung tissue and in KRT19 (148020)-positive epithelial cells, but not in CD31 (PECAM1; 173445)-positive endothelial cells, of patients with idiopathic pulmonary fibrosis (IPF; 178500) compared with controls. Transfer of Cav1 into mice suppressed bleomycin-induced IPF. Treatment of human pulmonary fibroblasts with TGFB (190180) decreased CAV1 mRNA and protein expression. CAV1 suppressed TGFB-induced extracellular matrix (ECM) production via the JNK (MAPK8; 601158) pathway, and it modulated SMAD (e.g., SMAD3; 603109) signaling by fibroblasts. Wang et al. (2006) concluded that CAV1 inhibits production of ECM molecules by fibroblasts and suggested that it may be a therapeutic target for IPF patients.
Trajkovski et al. (2011) demonstrated that the expression of microRNAs miR103 (613187) and miR107 (613189) is upregulated in obese mice. Silencing of miR103 and miR107 led to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR103/107 function in either liver or fat was sufficient to induce impaired glucose homeostasis. Trajkovski et al. (2011) identified caveolin-1, a critical regulator of the insulin receptor (INSR; 147670), as a direct target gene of miR103/107. They demonstrated that caveolin-1 is upregulated upon miR103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signaling, decreased adipocyte size, and enhanced insulin-stimulated glucose uptake. Trajkovski et al. (2011) concluded that their findings demonstrated the central importance of miR103/107 to insulin sensitivity and identified a new target for the treatment of type 2 diabetes and obesity.
Proteins that contain an F-BAR domain, such as PACSIN2 (604960), regulate membrane dynamics and bending. Senju et al. (2011) found that overexpression of the PACSIN2 F-BAR domain in HeLa cells altered the localization of CAV1 and caused mesh-like plasma membrane invaginations. The isolated F-BAR domain of PACSIN2 bound the N terminus of CAV1 more strongly than full-length PACSIN2. Senju et al. (2011) determined that an intramolecular interaction between the SH3 and F-BAR domains of PACSIN2 was autoinhibitory and that CAV1 interrupted this interaction. In addition to binding CAV1, the F-BAR domain of PACSIN2 simultaneously bound the plasma membrane and induced membrane tubulation. Knockdown of PACSIN2 in HeLa cells via small interfering RNA reduced the number of CAV1-positive invaginations, increased the diameter of caveolae necks, increased caveolae depth, and interfered with recruitment of dynamin-2 (DNM2; 602378) for caveolae fission.
Using various methods, Lanciotti et al. (2012) found that MLC1 (605908), TRPV4 (605427), HEPACAM (611642), syntrophin (see 601017), caveolin-1, Kir4.1 (KCNJ10; 602208), and AQP4 (600308) assembled into an Na,K-ATPase-associated multiprotein complex. In rat and human astrocyte cell lines, this Na,K-ATPase complex mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmotic stress. MLC1 associated directly with the Na,K-ATPase beta-1 subunit (ATP1B1; 182330), and plasma membrane expression of MLC1 was required for assembly of the Na,K-ATPase complex. TRPV4 was required for calcium influx, and AQP4 was recruited to the complex following hyposmotic stress.
The genes encoding murine caveolin-1 and -2 are colocalized within the A2 region of mouse chromosome 6 (Engelman et al., 1998). By FISH, Engelman et al. (1998) mapped CAV1 and CAV2 to chromosome 7q31.1-q31.2. (CA)n microsatellite repeat marker analysis of the CAV genomic clones indicated that they contain the marker D7S522, located at 7q31.1. Thus, Engelman et al. (1998, 1998) demonstrated that the 2 human genes map in a region of conserved synteny with murine 6-A2. The human CAV3 gene maps to 3p25, corresponding to the mouse region 6-E1.
Congenital Generalized Lipodystrophy, Type 3
In a 20-year-old woman, born of consanguineous Brazilian parents, with congenital generalized lipodystrophy type 3 (CGL3; 612526) with no mutation in the genes encoding either seipin (606158) or AGPAT2 (603100), Kim et al. (2008) identified a homozygous premature termination mutation in CAV1 (601047.0001). The mutation affected both the alpha and beta CAV1 isoforms and ablated CAV1 expression in skin fibroblasts. Kim et al. (2008) selected CAV1 as a candidate gene because of its involvement in insulin signaling and lipid homeostasis. CAV1 is a key structural component of plasma membrane caveolae, and Cav1-deficient mice display progressive loss of adipose tissue and insulin resistance. CAV1 mutations were not found in 3 additional patients with the disorder who did not have seipin or AGPAT2 mutations.
In 4 members of a large consanguineous family of Turkish origin with congenital generalized lipodystrophy type 3, Karhan et al. (2021) identified a homozygous frameshift mutation in the CAV1 gene (601047.0007). The mutation, which was identified by sequencing of a panel of genes involved in lipodystrophy or insulin resistance syndromes, was present in heterozygous state in the 7 unaffected parents who were tested. The variant was not present in the ExAC and gnomAD databases. By studying cultured skin fibroblasts from one of their patients and from the patient with CGL3 and the E38X mutation (601047.0001) reported by Kim et al. (2008), Karhan et al. (2021) found complete loss of protein expression of caveolin-1 and its partners caveolin-2 (601048) and cavin-1 (603198) and absence of caveolae at the plasma membrane. Patient fibroblasts also showed insulin resistance, increased oxidative stress, and premature senescence.
Familial Partial Lipodystrophy, Type 7
In a father and daughter with familial partial lipodystrophy type 7 (FPLD7; 606721), Cao et al. (2008) identified a heterozygous truncating mutation in the CAV1 gene (601047.0004). No coding sequence mutations were found in 4 other lipodystrophy-associated genes. The CAV1 gene was chosen for study because mouse models deficient in Cav1 show some similar features (Razani et al., 2002). The more severe neurologic phenotype in the daughter suggested that other factors, either genetic or nongenetic, can modulate the severity of the phenotype. An unrelated patient with partial lipodystrophy without ocular or neurologic findings had a heterozygous -88delC mutation in the 5-prime untranslated region of the CAV1 gene, with a potential effect on the reading frame. The 2 probands were ascertained from a cohort of 60 patients with partial lipodystrophy who were screened for CAV1 mutations.
In 2 unrelated patients with FPLD7, Garg et al. (2015) identified de novo heterozygous truncating mutations in the CAV1 gene (Q142X; 601047.0005 and F160X; 601047.0006). Patient fibroblasts showed significantly reduced expression of CAV1 compared to controls, but there were no differences in the number or morphology of caveolae compared to controls.
Primary Pulmonary Hypertension 3
In affected members of a 3-generation family with autosomal dominant primary pulmonary hypertension-3 (PPH3; 615343), Austin et al. (2012) identified a heterozygous truncating mutation in the CAV1 gene (601047.0002). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large exome control databases or 1,000 ethnically matched controls. Several unaffected family members also carried the mutation, indicating incomplete penetrance. The age at diagnosis ranged from 4 to 67 years, and later generations showed earlier onset of the disorder. CAV1 protein levels were decreased in patient fibroblasts compared to controls. Sequencing this gene in 260 additional patients with the disorder identified a de novo truncating mutation (601047.0003) in 1 patient with onset in infancy, suggesting that it is a rare cause of PPH. Patient lung tissue showed decreased CAV1 expression. Austin et al. (2012) suggested that both mutations may disrupt anchorage of caveolae to the plasma membrane. Cav1 knockout mice develop pulmonary hypertension (Drab et al., 2001; Zhao et al., 2002; Zhao et al., 2009), supporting the pathogenicity of the variants identified by Austin et al. (2012). The findings highlighted the importance of caveolae in the homeostasis of pulmonary vasculature.
Associations Pending Confirmation
In a 3-year-old female with a neonatal progeroid appearance, lipodystrophy, pulmonary hypertension, cutis marmorata, feeding difficulties, and failure to thrive, Schrauwen et al. (2015) identified heterozygous mutations in the CAV1, AGPAT2, and LPIN1 (605518) genes, all of which play an important role in triacylglycerol biosynthesis in adipose tissue.
By targeted disruption of caveolin-1, Drab et al. (2001) generated mice that lacked caveolae. The absence of this organelle impaired nitric oxide and calcium signaling in a cardiovascular system, causing aberrations in endothelium-dependent relaxation, contractility, and maintenance of myogenic tone. In addition, the lungs of knockout mice displayed thickening of alveolar septa caused by uncontrolled endothelial cell proliferation and fibrosis, resulting in severe physical limitations in caveolin-1-disrupted mice. Thus, Drab et al. (2001) concluded that caveolin-1 and caveolae play a fundamental role in organizing multiple signaling pathways in the cell.
By homologous recombination, Razani et al. (2001) created Cav1-null mice that were viable and fertile. In tissues and cultured embryonic fibroblasts from the Cav1-null mice, they observed a lack of caveolae formation, degradation and redistribution of Cav2, defects in the endocytosis of albumin (a caveolar ligand), and a hyperproliferative phenotype. In lung endothelial cells, the authors observed thickened alveolar septa and hypercellularity and an increase in the number of vascular endothelial growth factor receptor (191306)-positive endothelial cells. Cav1-null mice displayed exercise intolerance when compared with wildtype littermates in a swimming test. By measuring the physiologic response of aortic rings to various stimuli, Razani et al. (2001) determined that Cav1-deficient mice showed abnormal vasoconstriction and vasorelaxation responses. They observed that eNOS (NOS3; 163729) activity was upregulated in Cav1-null animals, and this activity could be blunted by a specific NOS inhibitor. Razani et al. (2001) concluded that Cav1 expression is required to stabilize the Cav2 protein product, to mediate the caveolar endocytosis of specific ligands, to negatively regulate the proliferation of certain cell types, and to provide tonic inhibition of eNOS activity in endothelial cells.
Razani et al. (2002) found that older Cav1-null mice had lower body weights and were resistant to diet-induced obesity compared to wildtype. Adipocytes from Cav1-null mice lacked caveolae membranes. Early on, a lack of Cav1 selectively affected only the female mammary gland fat pad and resulted in a nearly complete ablation of the hypodermal fat layer. With age, there was a systemic decompensation in lipid accumulation, resulting in smaller fat pads, reduced adipocyte cell diameter, and poorly differentiated/hypercellular white adipose parenchyma. Laboratory studies showed that Cav1-null mice had severely elevated triglyceride and free fatty acid levels, although insulin, glucose, and cholesterol levels were normal. The lean body phenotype and metabolic defects observed in these mice suggested a role for CAV1 in systemic lipid homeostasis in vivo.
To investigate the in vivo significance of caveolins in mammals, Zhao et al. (2002) generated mice deficient in the Cav1 gene and showed that, in its absence, no caveolae structures were observed in several nonmuscle cell types. Although the homozygous-null mice were viable, histologic examination and echocardiography identified a spectrum of characteristics of dilated cardiomyopathy in the left ventricular chamber of the Cav1-deficient hearts, including an enlarged ventricular chamber diameter, thin posterior wall, and decreased contractility. These animals also had marked right ventricular hypertrophy, suggesting a chronic increase in pulmonary artery pressure. Direct measurement of pulmonary artery pressure and histologic analysis revealed that the homozygous-null mice exhibited pulmonary hypertension, which may have contributed to the right ventricle hypertrophy. In addition, the loss of Cav1 led to a dramatic increase in systemic nitric oxide levels. Zhao et al. (2002) provided in vivo evidence that caveolin-1 is essential for the control of systemic nitric oxide levels and normal cardiopulmonary function.
Zhao et al. (2009) showed that pulmonary vascular remodeling and pulmonary hypertension in Cav1 -/- mice resulted from elevated Nos3 activity. Treatment of Cav1 -/- mice with either a superoxide scavenger or an NOS inhibitor reversed the phenotype. In Cav1 -/- mice, Nos3 activation resulted in impaired Pkg (PRKG1; 176894) activity through tyrosine nitration, and overexpression of Pkg countered the pulmonary hypertension in Cav1 -/- mice. Examination of lung tissue from patients with pulmonary arterial hypertension revealed elevated NOS3 activity, decreased CAV1 expression, and increased tyrosine nitration of PKG with concomitant compensatory elevation in PKG expression, recapitulating the observations in mice.
During vascular injury, proliferation and migration of smooth muscle cells leads to neointima formation, which is inhibited by carbon monoxide (CO), a byproduct of heme oxygenase-1 (HMOX1; 141250) activity. Kim et al. (2005) found that inhibition of intimal hyperplasia by CO in a rat vascular injury model involved enhanced expression of Cav1 in vascular smooth muscle via a signaling cascade involving cGMP and p38 MAPK (MAPK14; 600289). CO failed to inhibit cellular proliferation in the absence of Cav1 expression.
Yu et al. (2006) found that ligation of the left external carotid artery for 14 days to lower blood flow reduced the lumen diameter of carotid arteries from wildtype mice. In Cav1-null mice, the decrease in blood flow did not reduce the lumen diameter, but paradoxically increased wall thickness and cellular proliferation. In isolated pressurized carotid arteries, flow-mediated dilation was markedly reduced in Cav1-null arteries compared with those of wildtype mice. This impairment in response to flow was rescued by reconstituting Cav1 into the endothelium. Yu et al. (2006) concluded that endothelial Cav1 and caveolae are necessary for both rapid and long-term mechanotransduction in intact blood vessels.
Fernandez et al. (2006) found that Cav1-null mice exhibited impaired liver regeneration and low survival after partial hepatectomy. Hepatocytes showed dramatically reduced lipid droplet accumulation and did not advance through the cell division cycle. Treatment of Cav1-null mice with glucose, which is a predominant energy substrate when compared to lipids, drastically increased survival and reestablished progression of the cell cycle. Thus, Fernandez et al. (2006) concluded that caveolin-1 plays a crucial role in the mechanisms that coordinate lipid metabolism with the proliferative response occurring in the liver after cellular injury.
In a 20-year-old woman, born of consanguineous Brazilian parents, with congenital generalized lipodystrophy type 3 (CGL3; 612526), Kim et al. (2008) identified homozygosity for a c.112G-T transversion in exon 2 of the CAV1 gene that resulted in substitution of a premature termination codon for glu28 (E38X). This mutation affected both the alpha and beta CAV1 isoforms, consisting of residues 1 through 187 and 32 through 178, respectively. The E78X mutation occurred in heterozygosity in the unaffected mother and 2 sibs; the deceased father was inferred to have been heterozygous from haplotype analysis. The mutation was absent from 740 control chromosomes and from 277 random Brazilian individuals. The sequence of CAV1 was normal in 70 additional patients with lipodystrophy with mutations in either AGPAT2 (603100) or seipin (606158), indicating that CAV1 is not a modifier gene for this phenotype.
Karhan et al. (2021) studied cultured skin fibroblasts from the patient reported by Kim et al. (2008) and found complete loss of protein expression of caveolin-1 and its partners caveolin-2 (601048) and cavin-1 (603198) and absence of caveolae at the plasma membrane. The fibroblasts also showed insulin resistance, increased oxidative stress, and premature senescence.
In affected members of a 3-generation family with autosomal dominant primary pulmonary hypertension-3 (PPH3; 615343), Austin et al. (2012) identified a heterozygous 1-bp deletion (c.474delA) in exon 3 of the CAV1 gene, resulting in a frameshift and premature termination (Pro158ProfsTer22). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large exome control databases or in 1,000 ethnically matched controls. Several unaffected family members also carried the mutation, indicating incomplete penetrance. The age at diagnosis ranged from 4 to 67 years, and later generations showed earlier onset of the disorder. CAV1 protein levels were decreased in patient fibroblasts compared to controls. Austin et al. (2012) suggested that the mutation may disrupt anchorage of caveolae to the plasma membrane.
In a girl with primary pulmonary hypertension-3 (PPH3; 615343), Austin et al. (2012) identified a de novo heterozygous 1-bp deletion (c.473delC) in exon 3 of the CAV1 gene, resulting in a frameshift and premature termination (Pro158HisfsTer22) in a highly conserved site. The mutation was not found in either parent or in 1,000 ethnically matched controls. The patient also carried a second heterozygous CAV1 variant, V155I, which was found in her unaffected father and was predicted to be a tolerant substitution and thus not pathogenic. The patient was diagnosed with PPH at age 15 months, and lung biopsy showed medial thickening of the pulmonary arteries with persistent muscularization in the small peripheral arteries. Immunohistochemical studies showed decreased CAV1 expression in the pulmonary arteries compared to controls. Austin et al. (2012) suggested that the mutation may disrupt anchorage of caveolae to the plasma membrane.
In a father and daughter with familial partial lipodystrophy type 7 (FPLD7; 606721), Cao et al. (2008) identified a heterozygous 1-bp deletion in the CAV1 gene, resulting in a frameshift and premature termination (Ile134fsTer137). The mutation was not found in 1,063 controls. No coding sequence mutations were found in 4 other lipodystrophy-associated genes. The CAV1 gene was chosen for study because mouse models deficient in Cav1 show some similar features (Razani et al., 2002). The daughter had a more severe neurologic phenotype, suggesting that other factors, either genetic or nongenetic, can modulate the severity of the phenotype.
In a 7-year-old boy from Spain (patient NLD 1500.4) with familial partial lipodystrophy type 7 (FPLD7; 606721), Garg et al. (2015) identified a de novo heterozygous c.424C-T transition (chr7.116,199,228C-T, GRCh37) in exon 3 of the CAV1 gene, resulting in a gln142-to-ter (Q142X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases. Patient fibroblasts showed significantly reduced expression of CAV1 compared to controls, but there were no differences in the number or morphology of caveolae compared to controls.
In a 3-year-old girl (patient NLD 2800.5) with familial partial lipodystrophy type 7 (FPLD7; 606721), Garg et al. (2015) identified a de novo heterozygous 2-bp deletion (c.479_480delTT; chr7.116,199,282-116,199,283del, GRCh37) in exon 3 of the CAV1 gene, resulting in a frameshift and premature termination (Phe160Ter). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases. Patient fibroblasts showed significantly reduced expression of CAV1 compared to controls, but there were no differences in the number or morphology of caveolae compared to controls.
In 4 members of a large consanguineous family of Turkish descent with congenital generalized lipodystrophy type 3 (CGL3; 612526), Karhan et al. (2021) identified a homozygous 2-bp deletion (c.237_238del) in exon 3 of the CAV1 gene, resulting in a frameshift and premature termination (His79GlnfsTer3). The mutation, which was identified by sequencing of a panel of genes involved in lipodystrophy or insulin resistance syndromes, was present in the 7 unaffected parents who were tested. The variant was not present in the ExAC and gnomAD databases. By studying cultured skin fibroblasts from one patient, Karhan et al. (2021) found complete loss of protein expression of caveolin-1 and its partners caveolin-2 and cavin-1 and absence of caveolae at the plasma membrane. The fibroblasts also showed insulin resistance, increased oxidative stress, and premature senescence.
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