A Homozygous Mutation of Prelamin-A Preventing Its Farnesylation and Maturation Leads to a Severe Lipodystrophic Phenotype: New Insights into the Pathogenicity of Nonfarnesylated Prelamin-A
| Autor: | Stéphane Schneebeli, Véronique Béréziat, Jacqueline Capeau, Fawzi Bakiri, Caroline Le Dour, Françoise Darcel, Corinne Vigouroux, Martine Auclair, Marie-Anne Maubert, Yves Reznik, Olivier Lascols, Marie-Line Jacquemont, Dorota Jeziorowska |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Leptin Proband congenital hereditary and neonatal diseases and abnormalities Lipodystrophy Endocrinology Diabetes and Metabolism Clinical Biochemistry Laminopathy macromolecular substances Biology Biochemistry LMNA Young Adult Diabetes mellitus genetics Endocrinology Diabetes Mellitus medicine Humans Acanthosis Nigricans Protein Precursors Cellular Senescence Hypertriglyceridemia Prenylation Genetics integumentary system Biochemistry (medical) Nuclear Proteins nutritional and metabolic diseases Arrhythmias Cardiac Heterozygote advantage Fibroblasts Middle Aged Lamin Type A medicine.disease Phenotype Founder Effect Fatty Liver Oxidative Stress Mutation embryonic structures Mutation (genetic algorithm) Female Adiponectin Founder effect |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 96:E856-E862 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2010-2234 |
| Popis: | Mutations in LMNA, encoding A-type lamins, lead to multiple laminopathies, including lipodystrophies, progeroid syndromes, and cardiomyopathies. Alterations in the prelamin-A posttranslational maturation, resulting in accumulation of farnesylated isoforms, cause human progeroid syndromes. Accumulation of mutant nonfarnesylated prelamin-A leads to cardiomyopathy or progeria in mice, but no data have been provided in humans. OBJECTIVE, DESIGN, SETTING, AND PATIENTS: We searched for LMNA mutations in seven women originating from Reunion Island who were referred for a severe lipodystrophic syndrome. Clinical, molecular, genealogical, and cellular studies were performed in probands and relatives.The seven probands showed a severe partial lipodystrophic syndrome with diabetes and/or acanthosis nigricans, liver steatosis, hypertriglyceridemia, and low serum leptin and adiponectin levels. Three probands also had severe cardiac rhythm and conduction disturbances. We identified in all probands a homozygous LMNA p.T655fsX49 mutation leading to expression of a mutated prelamin-A with 48 aberrant C-terminal amino acids, preventing its physiological posttranslational farnesylation and maturation. Genealogical and haplotype analyses were consistent with a founder mutation transmitted from a common ancestor in the 17th century. In probands' cultured fibroblasts, mutated prelamin-A was associated with typical laminopathic nuclear dysmorphies, increased oxidative stress, and premature senescence. Heterozygous relatives were asymptomatic or partially affected, in favor of a codominant transmission of the disease with incomplete penetrance in heterozygotes.We reveal that a homozygous mutation of prelamin-A preventing its farnesylation leads to a severe lipodystrophic laminopathy in humans, which can be associated with cardiac conduction disturbances, stressing the pathogenicity of nonfarnesylated prelamin-A in human laminopathies. |
| Databáze: | OpenAIRE |
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