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Phenotypic and Genetic Heterogeneity in Congenital Generalized Lipodystrophy

Department of Internal Medicine (A.K.A., V.S., A.G.), Division of Nutrition and Metabolic Diseases and Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Internal Medicine (E.A.O.), University of Michigan, Ann Arbor, Michigan 48109; Diabetes Branch (S.A.M., P.G.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892; Department of Medicine (S.O.), Cambridge Medical School, Addenbrooke’s Hospital, United Kingdom CB2 2QR; Department of Dermatology (Z.Z.), Jinnah Postgraduate Medical Center, Karachi, Pakistan 75510; Department of Pediatric Gastroenterology (F.G.), Hacettepe University Medical Faculty, Ankara 06100, Turkey; Department of Pediatrics (S.A.A.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Pediatrics (A.K.), Bikur Cholim Hospital, Jerusalem 91004, Israel; Department of Pediatrics (A.R.), Children’s Hospital, Harvard University, Boston, Massachusetts 02115; Department of Pediatrics (N.H.W.), Washington University School of Medicine, St. Louis, Missouri 63110; Department of Pediatrics (L.B.), University Children’s Hospital, D-53113 Bonn, Germany; Department of Medicine (K.H.), Charles R. Drew University, Los Angeles, California 90059; Department of Endocrinology (K.K.), Mayo Clinic, Rochester, Minnesota 55905; Division of Endocrinology (S.B.P.), Medical University of South Carolina, Charleston, South Carolina 29403; and Department of Pediatrics (L.A.-G.), The United Arab Emirates University Faculty of Medicine and Health Services, Al Ain, United Arab Emirates

Address all correspondence and requests for reprints to: Dr. Abhimanyu Garg, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: abhimanyu.garg{at}utsouthwestern.edu.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.

This work was supported by the National Institutes of Health Grants R01-DK54387 and M01-RR00633 and by the Southwestern Medical Foundation.

A.K.A. and V.S. contributed equally to this work.

Abbreviations: AGPAT2, 1-Acylglycerol-3-phosphate O-acyltransferase 2; BSCL2, Berardinelli-Seip congenital lipodystrophy 2; CGL, congenital generalized lipodystrophy; SNP, single nucleotide polymorphism.

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