Mutations in the 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) gene have been identified in individuals affected with congenital generalized lipodystrophy (CGL).
Divergent metabolic phenotype between two sisters with congenital generalized lipodystrophy due to double AGPAT2 homozygous mutations. a clinical, genetic and in silico study.
We have demonstrated four novel mutations of the BSCL2 and AGPAT2 genes responsible for Berardinelli-Seip syndrome and Brunzell syndrome (AGPAT2-related syndrome).
In conclusion, our findings demonstrate that AGPAT2, which is mutated in patients with congenital generalized lipodystrophy and over-expressed in different types of cancer, is a direct transcriptional target of HIF-1, suggesting that upregulation of lipid storage by HIF-1 plays an important role in adaptation and survival of cancer cells under low oxygen conditions.
We sought to determine the plasma concentrations of leptin and adiponectin in patients with Berardinelli-Seip congenital lipodystrophy (BSCL) harboring mutations in the genes encoding either 1-acylglycerol-3-phosphate-O-acyltransferase-2 (AGPAT2) or BSCL2/seipin, in comparison with patients with other forms of inherited or acquired lipodystrophies or insulin receptor alterations.
To confirm the clinical hypothesis of congenital generalized lipodystrophy (CGL) or Berardinelli-Seip syndrome, the sequences of AGPAT2 (encoding for 1-acyl-sn-glycerol-3-phosphate acyltransferase beta) and BSCL2 (encoding for seipin) candidate genes were analyzed.
We discuss known inborn errors of CTGM, including deficiencies of: AGPAT2 (a form of generalized lipodystrophy), LPIN1 (childhood rhabdomyolysis), LPIN2 (an inflammatory condition, Majeed syndrome, described elsewhere in this issue), DGAT1 (protein loosing enteropathy), perilipin 1 (partial lipodystrophy), CGI-58 (gene ABHD5, neutral lipid storage disease (NLSD) with ichthyosis and "Jordan's anomaly" of vacuolated polymorphonuclear leukocytes), adipose triglyceride lipase (ATGL, gene PNPLA2, NLSD with myopathy, cardiomyopathy and Jordan's anomaly), hormone-sensitive lipase (HSL, gene LIPE, hypertriglyceridemia, and insulin resistance).
We studied the lipid profile of lymphoblastoid cell-lines from 20 BSCL patients with null mutations in the genes encoding either seipin (n=12) or AGPAT2 (n=8) in comparison to nine control cell-lines.
Twenty-two had genetic lipodystrophy: 12/22 familial partial lipodystrophy (FPLD) and 10/22 congenital generalized lipodystrophy (CGL), 8 with AGPAT2-linked CGL1 and 2 with seipin-linked CGL2.
Phenotypic heterogeneity in biochemical parameters correlates with mutations in AGPAT2 or Seipin genes among Berardinelli-Seip congenital lipodystrophy patients.
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.
We also detected two novel mutations (Val67Met and Leu19Arg) in children with syndromic forms of diabetes like Berardinelli Seip syndrome [1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)] and Fanconi Bickel syndrome [solute carrier family 2A2 (SLC2A2)].
Congenital generalized lipodystrophy or Berardinelli-Seip syndrome, autosomal recessive, is characterized by a complete early lipoatrophy and severe insulin resistance and results, in most cases, from mutations either in the seipin gene of unknown function or AGPAT2 encoding an enzyme involved in triacylglycerol synthesis.
In our subjects, there did not appear to be any distinguishing clinical characteristics between CGL subjects with AGPAT2 or Gng3lg mutations with the exception ofmental retardation in carriers of Gng3lg.
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder with two major subtypes, which are caused by AGPAT2 and BSCL2 mutations.
Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations.
Recently, we reported mutations in the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene in CGL pedigrees linked to chromosome 9q34 (CGL1 subtype), and mutations in the Seipin gene were reported in pedigrees linked to chromosome 11q13 (CGL2 subtype).
To analyze Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene variation in a Chinese boy with CGL and his family.
The phenotype and presence of two mutations suggests that biallelic mutations at PPARG cause a CGL similar to that observed with biallelic AGPAT2 or BSCL2 mutations.
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.
We also detected two novel mutations (Val67Met and Leu19Arg) in children with syndromic forms of diabetes like Berardinelli Seip syndrome [1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)] and Fanconi Bickel syndrome [solute carrier family 2A2 (SLC2A2)].