Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia

in European Journal of Endocrinology
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  • 1 Department of Pediatric Gastroenterology, Hepatology and Nutrition, Mersin University Faculty of Medicine, Mersin, Turkey
  • | 2 Sorbonne University, Inserm UMR_S938, Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, Paris, France
  • | 3 Department of Radiology, Mersin University Faculty of Medicine, Mersin, Turkey
  • | 4 Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
  • | 5 Sorbonne University, Inserm UMR_S1155, LUMIC, Tenon Imagery and Cytometry Platform, Paris, France
  • | 6 Nantes University, CNRS, Inserm UMR_S1087, Institut du Thorax, Nantes, France
  • | 7 Department of Endocrinology, Diabetology and Reproductive Endocrinology, Assistance Publique-Hôpitaux de Paris, Saint-Antoine University Hospital, National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
  • | 8 Department of Molecular Biology and Genetics, Assistance Publique-Hôpitaux de Paris, Saint-Antoine University Hospital, Paris, France

Correspondence should be addressed to A N Karhan or C Vigouroux; Email: asunurkar83@gmail.com or corinne.vigouroux@inserm.fr
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Objective

CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling 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.

Supplementary Materials

    • Supplemental Table 1 Antibodies used in Western Blot studies

 

     European Society of Endocrinology

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