Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.
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.
Agarwal
Anil K
AK
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.
Simha
Vinaya
V
Oral
Elif Arioglu
EA
Moran
Stephanie A
SA
Gorden
Phillip
P
O'Rahilly
Stephen
S
Zaidi
Zohra
Z
Gurakan
Figen
F
Arslanian
Silva A
SA
Klar
Aharon
A
Ricker
Alyne
A
White
Neil H
NH
Bindl
Lutz
L
Herbst
Karen
K
Kennel
Kurt
K
Patel
Shailesh B
SB
Al-Gazali
Lihadh
L
Garg
Abhimanyu
A
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
C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits; D000217:Acyltransferases; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D020962:Heterotrimeric GTP-Binding Proteins