Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 96, Issue 5, Pages E856-E862Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2010-2234
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Funding
- French Institut National de la Sante et de la Recherche Medicale
- European Union [LSHM-CT-2005-018690]
- French Ministere de l'Enseignement Superieur et de la Recherche
- French Institut National de la Sante et de la Recherche Medicale
- European Union [LSHM-CT-2005-018690]
- French Ministere de l'Enseignement Superieur et de la Recherche
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Context: 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. Results: 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 homozygousLMNAp.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. Conclusions: 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. (J Clin Endocrinol Metab 96: E856-E862, 2011)
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