title: Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Nutrition and Metabolic Diseases and Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: Vinaya
authors.initials: V
authors.lastname: Simha
authors.forename: Elif Arioglu
authors.initials: EA
authors.lastname: Oral
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Moran
authors.forename: Phillip
authors.initials: P
authors.lastname: Gorden
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Zohra
authors.initials: Z
authors.lastname: Zaidi
authors.forename: Figen
authors.initials: F
authors.lastname: Gurakan
authors.forename: Silva A
authors.initials: SA
authors.lastname: Arslanian
authors.forename: Aharon
authors.initials: A
authors.lastname: Klar
authors.forename: Alyne
authors.initials: A
authors.lastname: Ricker
authors.forename: Neil H
authors.initials: NH
authors.lastname: White
authors.forename: Lutz
authors.initials: L
authors.lastname: Bindl
authors.forename: Karen
authors.initials: K
authors.lastname: Herbst
authors.forename: Kurt
authors.initials: K
authors.lastname: Kennel
authors.forename: Shailesh B
authors.initials: SB
authors.lastname: Patel
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D000217:Acyltransferases / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D002899:Chromosomes, Human, Pair 9; D004252:DNA Mutational Analysis; D005260:Female; D044388:GTP-Binding Protein gamma Subunits; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008060:Lipodystrophy / Q000151:congenital / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits; D000217:Acyltransferases; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D020962:Heterotrimeric GTP-Binding Proteins