Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia

Abstract

Objective : CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signalling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic and cellular characteristics of CGL3. Design/Methods: In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Results: Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n=9) were asymptomatic, without any metabolic abnormality. Patients’ fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients’ fibroblasts also displayed insulin resistance, increased oxidative stress and premature senescence. Conclusions: The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.

HD-PTP/PTPN23 hypomorphic mice display lipodystrophy

“…While PTPN23 H/H IAT adipocytes exhibit reduced volume and lipid droplet size, RPPA analysis revealed PTPN23 H/H IAT has increased levels of lipid synthesis enzymes Acetyl Co-A Synthase, Acetyl-CoA Carboxylase and Fatty Acid Synthase (Figure 4C), suggesting that PTPN23 H/H IAT is subject to altered regulation of lipid storage rather than defects in the lipid biogenesis machinery itself. In addition, PTPN23 H/H IAT exhibited reduced Caveolin-1 levels (Figure 4C), which is interesting as Caveolin-1 has been implicated in regulating lipid droplet homeostasis [77,78] and mutations in CAV1 are linked to lipodystrophy [79][80][81][82]. Additionally, Caveolin-1 physically interacts with HD-PTP [83].…”

Structural characterization of a breast cancer-associated mutation in caveolin-1

“…In addition to P132L, a variety of other pathogenic mutations in caveolins have been identified in humans (12,44,45,(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). The most direct equivalent to P132L is a P105L mutation in CAV3 associated with muscular dystrophy (56,57).…”

Molecular and Cellular Bases of Lipodystrophy Syndromes

“…Digestive signs are frequent in neonates or infants with CGL. In late infancy or adolescence, dysphagia can reveal megaesophagus, due to esophageal achalasia, in CGL due to pathogenic variants of CAVIN1 or CAV1, encoding proteins involved in the formation of caveolae at the cell plasma membrane (73)(74)(75)(76)(77). Growth disorders, dysmorphic features with micrognathia, beaked nose, dental crowding, prominent eyes, dystrophic bones, and/or signs suggesting accelerated aging such as precocious whitening and/ or loss of hair, sclerodermatous skin appearance, joint limitations, and/or muscle atrophy are hallmarks of progeroid lipodystrophies (67,78,79).…”