title: Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects.
abstract: 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), IVS3-1G-->C, and C636A (Phe189X). In three siblings with Brunzell syndrome, we identified a splice site mutation (IVS4-2A-->G) 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.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. mfu@medicine.umaryland.edu
authors.forename: Mao
authors.initials: M
authors.lastname: Fu
authors.forename: Rasa
authors.initials: R
authors.lastname: Kazlauskaite
authors.forename: Maria de Fátima Paiva
authors.initials: Mde F
authors.lastname: Baracho
authors.forename: Maria Goretti Do Nascimento
authors.initials: MG
authors.lastname: Santos
authors.forename: José
authors.initials: J
authors.lastname: Brandão-Neto
authors.forename: Sandra
authors.initials: S
authors.lastname: Villares
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Celi
authors.forename: Bernardo L
authors.initials: BL
authors.lastname: Wajchenberg
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D000217:Acyltransferases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D016368:Frameshift Mutation; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D008060:Lipodystrophy / Q000151:congenital / Q000235:genetics*; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits; D022821:RNA Splice Sites; D000217:Acyltransferases; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase