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Molecular Scanning of ß-3-Adrenergic Receptor Gene in Total Congenital Lipoatrophic Diabetes Mellitus¹

Johns Hopkins University School of Medicine, Division of Endocrinology and Metabolism (K.S.), Division of Geriatric Medicine and Gerontology (J.W., A.R.S.), Division of Pediatric Endocrinology (L.P.), Baltimore, Maryland 21287; Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (S.I.T.), Bethesda, Maryland 20892; and the Joslin Diabetes Center (C.R.K.), Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Kristi Silver, 725 West Lombard Street, Room S-415, Baltimore, MD 21201. E-mail: ksilver{at}umppa1.ab.umd.edu

Total congenital lipoatrophic diabetes is characterized by absence of subcutaneous adipose tissue, hypertriglyceridemia, and insulin resistance. We hypothesized that mutations in the ß-3-adrenergic receptor (ß3AR) gene might result in the lipoatrophic phenotype by preventing triglyceride storage in adipocytes; thereby, resulting in secondary insulin resistance. We screened the ß3AR gene in 7 subjects with total congenital lipoatropic diabetes. We found a heterozygous substitution of a guanine to cytosine at position -153 (G-153C) in the 5'-untranslated region of 3 African-American lipoatrophic siblings and 1 sibling without lipoatrophy but with insulin resistance. To determine whether the base change was related to the lipoatrophic phenotype, we genotyped 69 African-Americans without lipoatrophy and found the G-153C substitution in 2 control subjects (allele frequency = 0.01). No other single-stranded polymorphism variants were found in any of the 7 lipoatrophic subjects. Direct sequencing of both alleles of 1 lipoatrophic subject demonstrated a thymidine insertion at position -300 in both alleles. All lipoatrophic subjects along with 20 African-American control subjects were homozygous for the base insertion, suggesting an error in the published sequence. In conclusion, mutations in the ß3AR gene do not appear to be involved in the development of congenital total lipoatrophy.

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