Divergent metabolic phenotype between two sisters with congenital generalized lipodystrophy due to double AGPAT2 homozygous mutations. a clinical, genetic and in silico study
| Autor: | José Luis Santos, Carlos F. Lagos, Víctor Cortés, Susan V. Smalley, Denisse Goldenberg, María Isabel Hodgson |
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| Rok vydání: | 2013 |
| Předmět: |
Leptin
Models Molecular Anatomy and Physiology DNA Mutational Analysis lcsh:Medicine Biochemistry Congenital generalized lipodystrophy Exon Endocrinology Autosomal Recessive Integrative Physiology Missense mutation Insulin lcsh:Science Genetics Multidisciplinary Homozygote Fatty Acids Phenotype Lipids Receptors Leptin Medicine Female Lipodystrophy Research Article Adult In silico Endocrine System Biology Bioenergetics Lipodystrophy Congenital Generalized Genetic Mutation medicine Humans Genetic Predisposition to Disease Obesity Congenital Hereditary Myopathies Nutrition Clinical Genetics Diabetic Endocrinology Leptin receptor Base Sequence Endocrine Physiology Point mutation Siblings lcsh:R Human Genetics Diabetes Mellitus Type 2 medicine.disease Lipid Metabolism Protein Structure Tertiary Metabolism Metabolic Disorders Mutation lcsh:Q Physiological Processes Acyltransferases |
| Zdroj: | PLoS ONE PLOS ONE Artículos CONICYT CONICYT Chile instacron:CONICYT PLoS ONE, Vol 9, Iss 1, p e87173 (2014) |
| ISSN: | 1932-6203 |
| Popis: | Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Missense mutation c.299G>A changes a conserved serine in the acyltransferase NHX4D motif of AGPAT2 (p.Ser100Asn). Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations. |
| Databáze: | OpenAIRE |
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