This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fu, M. Articles by Shuldiner, A. R. Search for Related Content PubMed PubMed Citation Articles by Fu, M. Articles by Shuldiner, A. R.

Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip Congenital Lipodystrophy and Brunzell Syndrome: Phenotype Variability Suggests Important Modifier Effects

Division of Endocrinology, Diabetes and Nutrition (M.F., F.S.C., A.R.S.), University of Maryland School of Medicine, and Geriatrics Research and Education Clinical Center (A.R.S.), Baltimore Veterans Administration Medical Center, Baltimore, Maryland 21201; Division of Endocrinology (R.K.), Cook County Hospital, Chicago, Illinois 60612; Center of Health Sciences (M.d.F.P.B., M.G.D.N.S., J.B.-N.), Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil 59010-180; and Endocrine Service (S.V., B.L.W.), Hospital das Clinicas, University of Sao Paulo, Brazil 05403-900

Address all correspondence and requests for reprints to: Mao Fu, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 West Redwood Street, Baltimore, Maryland 21201. E-mail: mfu{at}medicine.umaryland.edu.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder caused by mutations in AGPAT2 and Gng3lg. We screened for mutations in AGPAT2 and Gng3lg in 26 families with CGL and one family with Brunzell syndrome. We found mutations in either AGPAT2 or Gng3lg in all but four probands, including three novel mutations in AGPAT2, A712T (Lys215X), IVS3-1GC, and C636A (Phe189X). In three siblings with Brunzell syndrome, we identified a splice site mutation (IVS4–2AG) in AGPAT2, showing that AGPAT2 mutations can also cause Brunzell syndrome. Eighteen CGL patients from 15 families from the same region of northeastern Brazil were homozygous for a frameshift mutation (669insA of AF05149) in Gng3lg. Despite having the same mutation, the subjects had widely divergent clinical manifestations. In our subjects, there did not appear to be any distinguishing clinical characteristics between CGL subjects with AGPAT2 or Gng3lg mutations with the exception of mental retardation in carriers of Gng3lg. In summary, mutations in AGPAT2 and Gng3lg are approximately equally represented in CGL; despite harboring the same Gng3lg mutation, subjects may have widely divergent clinical manifestations, suggesting modifying influences of other genes and/or environment; and Brunzell syndrome may be caused by a mutation in AGPAT2.

This work was supported by Research Grants R01-DK54261 and K24-DK02673, awarded by the National Institutes of Health, the American Diabetes Association, and the Baltimore Veterans Administration Geriatric Research and Education Clinical Center.

Abbreviations: BSCL, Berardinelli-Seip syndrome; CGL, congenital generalized lipodystrophy; OMIM, Online Mendelian Inheritance in Man; UTR, untranslated region.

This article has been cited by other articles:

				D. Ito and N. Suzuki Seipinopathy: a novel endoplasmic reticulum stress-associated disease Brain, September 12, 2008; (2008) awn216v1. [Abstract] [Full Text] [PDF]

				R. A. Hegele, T. R. Joy, S. A. Al-Attar, and B. K. Rutt Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism J. Lipid Res., July 1, 2007; 48(7): 1433 - 1444. [Abstract] [Full Text] [PDF]

				J R Porter and T G Barrett Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and {beta} cell failure J. Med. Genet., December 1, 2005; 42(12): 893 - 902. [Abstract] [Full Text] [PDF]

				Y.-H. Yu and H. N. Ginsberg Adipocyte Signaling and Lipid Homeostasis: Sequelae of Insulin-Resistant Adipose Tissue Circ. Res., May 27, 2005; 96(10): 1042 - 1052. [Abstract] [Full Text] [PDF]