Alternative titles; symbols
HGNC Approved Gene Symbol: AGPAT2
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38) : 9:136,673,143-136,687,457 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Lipodystrophy, congenital generalized, type 1 | 608594 | Autosomal recessive | 3 |
Lysophosphatidic acid (LPA) is a phospholipid with diverse biologic activities. LPA acyltransferase (LPAAT), or 1-acyl-sn-glycerol-3-phosphate acetyltransferase (EC 2.3.1.51), catalyzes the conversion of LPA to PA. By searching an EST database for human homologs of yeast LPAAT, West et al. (1997) identified cDNAs encoding 2 proteins, which they designated LPAAT-alpha (603099) and LPAAT-beta. The predicted LPAAT-beta protein is 278 amino acids long. Overall, the sequences of the 2 human proteins are 12% identical to the sequence of yeast LPAAT. Northern blot analysis revealed that, unlike LPAAT-alpha, LPAAT-beta is expressed in a distinct tissue-specific pattern, with the highest levels of expression observed in liver and heart.
Lu et al. (2005) cloned mouse Agpat2. The deduced 278-amino acid protein has a putative N-terminal signal sequence and 3 transmembrane domains. It contains catalytic and substrate-binding motifs and a third motif conserved among AGPAT family members. Mouse and human AGPAT2 share 76% amino acid identity. RT-PCR analysis of mouse tissues detected highest expression in liver, followed by kidney, gut, skeletal muscle, and heart. All other tissues showed little to no expression.
West et al. (1997) demonstrated that human LPAAT-alpha and LPAAT-beta complemented an E. coli LPAAT mutation. Overexpression of the human LPAATs in mammalian cell lines led to increased enzyme activity. This increase in activity correlated with enhanced transcription and synthesis of IL6 (147620) and TNF-alpha (191160), suggesting that LPAAT overexpression may amplify the cellular response to cytokine stimulation.
Using RT-PCR, Lu et al. (2005) found that activation of Ppar-alpha (170998) in mouse heart elevated Agpat2 expression.
Eberhardt et al. (1997) reported that the LPAAT-beta gene contains 6 exons and spans less than 20 kb.
By fluorescence in situ hybridization, Eberhardt et al. (1997) mapped the LPAAT-beta gene to 9q34.3. Aguado and Campbell (1998) observed that the LPAAT-alpha gene is located at 6p21, making the LPAAT genes another example of 2 members of a gene family being found at 9q34 and 6p21. The authors suggested that the 2 chromosomal regions arose from duplication of an ancestral chromosomal segment.
Lu et al. (2005) mapped the mouse Agpat2 gene to chromosome 2.
In affected members of 11 pedigrees with autosomal recessive Berardinelli-Seip congenital lipodystrophy showing linkage to 9q34 (CGL1; 608594), Agarwal et al. (2002) identified 11 mutations in the AGPAT2 gene (see, e.g., 603100.0001-603100.0005). All affected members carried homozygous or compound heterozygous mutations. The AGPAT2 enzyme catalyzes an essential reaction in the biosynthetic pathway of glycerophospholipids and triacylglycerol. Agarwal et al. (2002) suggested that the AGPAT2 enzyme is likely to affect triacylglycerol synthesis in adipose tissue, and that mutations may cause lipodystrophy by resulting in triglyceride-depleted adipocytes.
Fu et al. (2004) screened for mutations in AGPAT2 and BSCL2 (606158) in 27 families with congenital generalized lipodystrophy. They found mutations in either AGPAT2 or BSCL2 in all but 4 probands, including 3 novel mutations in AGPAT2, lys215 to ter (603100.0006), IVS3-1G-C (603100.0007), and phe189 to ter (603100.0008). In 3 sibs with congenital generalized lipodystrophy and cystic angiomatosis of long bones (a phenotypic variant known as Brunzell syndrome), they identified a splice site mutation in AGPAT2 (IVS4-2A-G; 603100.0002). Fu et al. (2004) concluded that there did not appear to be any distinguishing clinical characteristics between subjects with congenital generalized lipodystrophy with AGPAT2 or BSCL2 mutations with the exception of mental retardation in carriers of BSCL2.
In 5 patients from 3 families (families 3-5) with CGL1, Gunes et al. (2020) identified homozygous mutations in the AGPAT2 gene (603100.0010-603100.0012). The mutations were identified by whole-exome sequencing of the 4 genes previously associated with congenital lipodystrophy. Functional studies were not performed.
In affected sibs from 2 unrelated families segregating Berardinelli-Seip congenital lipodystrophy-1 (CGL1; 608594), one from Turkey and the other from Belgium, Agarwal et al. (2002) found a 202C-T transition in the AGPAT2 gene in homozygous state, leading to an arg68-to-ter (R68X) amino acid change. In one family the 2 sibs were 50 and 53 years old; in the other, the 2 sibs were 15 and 17 years old.
In affected members of 5 families of African descent with Berardinelli-Seip congenital lipodystrophy-1 (CGL1; 608594), Agarwal et al. (2002) found either homozygosity or compound heterozygosity for a splice site mutation in the AGPAT2 gene (IVS4-2A-G) resulting in a frameshift and a premature termination at codon 228 (Gln196fsTer228). In 2 African American families living in the U.S., the mutation was present in homozygous state. In another U.S. African American family, it was present in compound heterozygous state with a 1-bp insertion, 377insT, causing a frameshift, Leu126fsTer146 (603100.0003). In a Caribbean family living in the U.K., it was found in compound heterozygous state with a missense mutation, leu228 to pro (603100.0004). In an African Caribbean family living in Trinidad, it was present in compound heterozygous state with a 3-bp deletion, 418delTTC (603100.0005), resulting in loss of phenylalanine-140. The 4 homozygous individuals in 2 families varied in age from 23 to 37 years. Agarwal et al. (2002) found that the splice site mutation in the 5 families of African origin was on an allele that had the same haplotype for 7 markers extending 33 kb, suggesting a common ancestral mutation.
Fu et al. (2004) found this mutation in an African American female with congenital generalized lipodystrophy and in 3 African American sibs with cystic angiomatosis of the long bones (a phenotype designated Brunzell syndrome; see 608594). In the African American sibship, the 2 females had primary amenorrhea.
In a U.S. African American family, Agarwal et al. (2002) found that 2 individuals, aged 29 and 31 years, with congenital generalized lipodystrophy-1 (CGL1; 608594) were compound heterozygotes for the AGPAT2 IVS4-2A-G splice site mutation (603100.0002) and a 1-bp deletion, 377insT, which caused a frameshift mutation beginning with leu126 and ending with premature termination at codon 146.
In an African Caribbean family living in the U.K., Agarwal et al. (2002) found that affected members with congenital generalized lipodystrophy-1 (CGL1; 608594) were compound heterozygotes for mutations of the AGPAT2 gene: the IVS4 acceptor splice mutation (603100.0002) and a missense mutation, leu228 to pro (L228P), resulting from a 683T-C transition. The affected individuals were 13 and 15 years old.
In an African Caribbean family from Trinidad with congenital generalized lipodystrophy-1 (CGL1; 608594), Agarwal et al. (2002) found that 1 affected individual, a 3-year-old female, was a compound heterozygote for the AGPAT2 intron 4 acceptor splice site mutation (603100.0002) and a 3-bp deletion, 418delTTC, causing deletion of phenylalanine at codon 140.
In 2 female sibs from an African American family with congenital generalized lipodystrophy-1 (CGL1; 608594), Fu et al. (2004) found homozygosity for an A-to-T transversion at nucleotide 712 in exon 5 of the AGPAT2 gene that caused lys215 of the protein to be replaced by a premature termination codon (K215X).
In an individual from Brazil of African descent with congenital generalized lipodystrophy-1 (CGL1; 608594) Fu et al. (2004) found compound heterozygosity for mutations in the AGPAT2 gene. One allele carried a splice site mutation (IVS3-1G-C); the other carried a premature termination mutation (603100.0008). The IVS3-1G-C mutation predicted frameshift and premature termination (Asn164fsTer249).
Fu et al. (2004) found that 1 AGPAT2 allele of a Brazilian individual with congenital generalized lipodystrophy-1 (CGL1; 608594) contained a C-to-A transversion at nucleotide 636 in exon 4 that resulted in a premature termination at phe189 (F189X). The other allele carried a splice site mutation (603100.0007).
In all 10 affected members from 2 families with congenital generalized lipodystrophy-1 (CGL1; 608594) from southeastern Brazil, Gomes et al. (2004) identified homozygosity for a 1.036-bp deletion encompassing nucleotide 50 of exon 3 to nucleotide 534 within intron 4 of the AGPAT2 gene, resulting in the skipping of exons 3 and 4 and inducing the deletion of nucleotides 317-588. The mutation causes a frameshift and premature termination codon, Gly106fsTer188. Gomes et al. (2004) noted that this mutation had previously been described in a large consanguineous pedigree from Portugal by Agarwal et al. (2002).
In a patient, born of consanguineous Turkish parents (family 3), with congenital lipodystrophy-1 (CGL1; 608594), Gunes et al. (2020) identified homozygosity for a c.685G-T transversion in the AGPAT2 gene, resulting in a glu229-to-ter (E229X) substitution. The mutation was identified by whole-exome sequencing of 4 genes associated with lipodystrophy. Functional studies were not performed.
In 2 sibs, born of consanguineous Turkish parents (family 4), with congenital lipodystrophy-1 (CGL1; 608594), Gunes et al. (2020) identified homozygosity for a c.316+1G-T transversion in the AGPAT2 gene, resulting in a splicing abnormality. The mutation was identified by whole-exome sequencing of 4 genes associated with lipodystrophy. Functional studies were not performed.
In 2 sibs, born of consanguineous Turkish parents (family 5), with congenital lipodystrophy-1 (CGL1; 608594), Gunes et al. (2020) identified homozygosity for a c.514G-A transition in the AGPAT2 gene, resulting in a glu172-to-lys (E172K) substitution. The mutation was identified by whole-exome sequencing of 4 genes associated with lipodystrophy. Functional studies were not performed.
Agarwal, A. K., Arioglu, E., de Almeida, S., Akkoc, N., Taylor, S. I., Bowcock, A. M., Barnes, R. I., Garg, A. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nature Genet. 31: 21-23, 2002. [PubMed: 11967537] [Full Text: https://doi.org/10.1038/ng880]
Aguado, B., Campbell, R. D. Characterization of a human lysophosphatidic acid acyltransferase that is encoded by a gene located in the class III region of the human major histocompatibility complex. J. Biol. Chem. 273: 4096-4105, 1998. [PubMed: 9461603] [Full Text: https://doi.org/10.1074/jbc.273.7.4096]
Eberhardt, C., Gray, P. W., Tjoelker, L. W. Human lysophosphatidic acid acyltransferase: cDNA cloning, expression, and localization to chromosome 9q34.3. J. Biol. Chem. 272: 20299-20305, 1997. [PubMed: 9242711] [Full Text: https://doi.org/10.1074/jbc.272.32.20299]
Fu, M., Kazlauskaite, R., de Fatima Paiva Baracho, M., Do Nascimento Santos, M. G., Brandao-Neto, J., Villares, S., Celi, F. S., Wajchenberg, B. L., Shuldiner, A. R. Mutations in Gng31g and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects. J. Clin. Endocr. Metab. 89: 2916-2922, 2004. [PubMed: 15181077] [Full Text: https://doi.org/10.1210/jc.2003-030485]
Gomes, K. B., Fernandes, A. P., Ferreira, A. C. S., Pardini, H., Garg, A., Magre, J., Pardini, V. C. Mutations in the seipin and AGPAT2 genes clustering in consanguineous families with Berardinelli-Seip congenital lipodystrophy from two separate geographical regions of Brazil. J. Clin. Endocr. Metab. 89: 357-361, 2004. [PubMed: 14715872] [Full Text: https://doi.org/10.1210/jc.2003-030415]
Gunes, N., Kutlu, T., Tekant, G. T., Eroglu, A. G., Ustundag, N. C., Ozturk, B., Onay, H., Tuysuz, B. Congenital generalized lipodystrophy: The evaluation of clinical follow-up findings in a series of five patients with type 1 and two patients with type 4. Europ. J. Med. Genet. 63: 103819, 2020. [PubMed: 31778856] [Full Text: https://doi.org/10.1016/j.ejmg.2019.103819]
Lu, B., Jiang, Y. J., Zhou, Y., Xu, F. Y., Hatch, G. M., Choy, P. C. Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPAR-alpha in murine heart. Biochem. J. 385: 469-477, 2005. [PubMed: 15367102] [Full Text: https://doi.org/10.1042/BJ20041348]
West, J., Tompkins, C. K., Balantac, N., Nudelman, E., Meengs, B., White, T., Bursten, S., Coleman, J., Kumar, A., Singer, J. W., Leung, D. W. Cloning and expression of two human lysophosphatidic acid acyltransferase cDNAs that enhance cytokine-induced signaling responses in cells. DNA Cell Biol. 16: 691-701, 1997. [PubMed: 9212163] [Full Text: https://doi.org/10.1089/dna.1997.16.691]