Submission Details

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.