Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia
| Autor: | Olivier Lascols, Asuman Nur Karhan, Jamila Zammouri, Jocelyne Magré, Isabelle Jéru, Fehmi Ates, Marie-Christine Verpont, Bruno Fève, Martine Auclair, Yusuf Usta, E. Capel, Feramuz Demir Apaydin, Corinne Vigouroux |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_specialty Adolescent Endocrinology Diabetes and Metabolism Caveolin 2 Caveolin 1 030209 endocrinology & metabolism Caveolae Asymptomatic Neonatal Progeroid Syndrome Congenital generalized lipodystrophy 03 medical and health sciences Consanguinity 0302 clinical medicine Endocrinology Insulin resistance Lipodystrophy Congenital Generalized Microscopy Electron Transmission Internal medicine Retinitis pigmentosa medicine Humans Child Index case Cellular Senescence 030304 developmental biology Dyslipidemias 0303 health sciences business.industry Generalized lipodystrophy Homozygote Infant RNA-Binding Proteins General Medicine Fibroblasts medicine.disease 3. Good health Pedigree Esophageal Achalasia Oxidative Stress Child Preschool Female medicine.symptom business |
| Zdroj: | European journal of endocrinology. 185(6) |
| ISSN: | 1479-683X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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