The AGPAT2 enzyme catalyzes the acylation of the lysophosphatidic acid at the sn-2 position to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. High expression of AGPAT2 mRNA in adipose tissue compared with other isoforms suggests that the mutations might affect the adipose tissue the most. Although the precise mechanisms by which AGPAT2 mutations cause lipodystrophy remain unclear, the lack of triglyceride synthesis in the adipocytes or reduced bioavailability of phosphatidic acid and glycerophospholipids such as, phosphatidylinositol, phosphatidylcholine, and phosphatidylethanolamine, which are essential components of cell membranes and play an important in intracellular signaling, could be responsible.
The AGPAT2 gene contains 6 exons and spans less than 20 kb.
Heathcote et al. (2002) identified 16 subjects with congenital generalized lipodystrophy from 11 consanguineous sibships in Oman originating from three different geographical areas (groups A, B, and C). Heathcote et al. (2002) used a homozygosity mapping approach to investigate the genes involved in these forms of congenital generalized lipodystrophy. Upon investigating the 9q34 locus (BSCL1), two families from group A (A4 and A5) and four from group C (C1 to C4) showed homozygosity for either D9S1818 or D9S1826 markers (which had an interval of 9 cM with no identified markers in between). On the other hand, one of the patients' mother and brother, both unaffected, showed homozygosity for both the markers, just as the patient himself. Neither Group B nor the fifth family of group C showed linkage to BSCL1 locus and further analysis of this locus could be possible only with identification of markers between the above markers. Three families from group A showed mutations in the BSCL2 gene, and Heathcote et al. (2002) suggested the existence of two or more novel loci for autosomal recessive CGL in the Omani population. In 2002, Rajab et al. 17 children with congenital generalized lipodystrophy from 12 consanguineous sibships; including those analyzed by Heathcote et al. (2002). Rajab et al. (2002) presented evidence for at least one further form of congenital generalized lipodystrophy that did not show involvement of either of the 2 loci, AGPAT2 and BSCL2, and suggested that this group may represent a new clinical syndrome with lipodystrophy at a different locus.
Agarwal et al. (2003) analyzed a consanguineous family from Palestine with congenital generalized lipodystrophy. Of a total of three siblings, a 9-year-old female was homozygous for the disease. Genotyping showed no substantial alterations in the coding regions of the BSCL2 and AGPAT2 genes. It is likely that a mutation in a yet unmapped gene resulted in the observed phenotype.
Agarwal et al. (2003) analyzed a consanguineous family of African origin from the United Arab Emirates with congenital generalized lipodystrophy. Of a total of seven siblings, a 7-year-old male was homozygous for the disease. Genotyping revealed that he was homozygous for the IVS4-2 A-G mutation in the AGPAT2 gene. The mutation is expected to cause a frameshift and a premature termination at codon 228. Agarwal et al. (2003) analyzed other affected individuals with African origin and found that the IVS4-2 A-G mutation is highly prevalent in these patients. In addition, the mutation in most of these individuals shared a common haplotype spanning 33 kb around the mutation, including dinucleotide repeat markers and SNPs, thus, suggestive of a common ancestral origin.