AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34

Agarwal, Anil K.; Arioǧlu, Elif; Almeida, Salomé de; Akkoç, Nurullah; Taylor, Simeon I.; Bowcock, Anne M.; Barnes, R. Bowling; Garg, Abhimanyu

doi:10.1038/ng880

Cited by 470 publications

(350 citation statements)

References 15 publications

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“…Genetic mutation of LD-related proteins such as, seipin (Magre et al 2001), caveolin-1 (Kim et al 2008), PTRF/cavin1 (Hayashi et al 2009;Rajab et al 2010), and 1-acylglycerol-3-phosphate-O-acyltransferase 2 (Agarwal et al 2002), which is a critical enzyme in TG and phospholipid synthesis, has been shown to cause lipodystrophies. The mechanism that seipin mutation leads to lipodystrophy may not be directly related to its effect on LD formation because it also affects a transcriptional cascade that drives adipogenesis (Payne et al 2008;Chen et al 2009).…”

Section: Lipid Droplets and Disease Diseases Related To Lipid Storagementioning

confidence: 99%

Not Just Fat: The Structure and Function of the Lipid Droplet

Fujimoto

Parton²

2011

Cold Spring Harbor Perspectives in Biology

392

336

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Lipid droplets (LDs) are independent organelles that are composed of a lipid ester core and a surface phospholipid monolayer. Recent studies have revealed many new proteins, functions, and phenomena associated with LDs. In addition, a number of diseases related to LDs are beginning to be understood at the molecular level. It is now clear that LDs are not an inert store of excess lipids but are dynamically engaged in various cellular functions, some of which are not directly related to lipid metabolism. Compared to conventional membrane organelles, there are still many uncertainties concerning the molecular architecture of LDs and how each function is placed in a structural context. Recent findings and remaining questions are discussed.

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Section: Lipid Droplets and Disease Diseases Related To Lipid Storagementioning

confidence: 99%

Not Just Fat: The Structure and Function of the Lipid Droplet

Fujimoto

Parton²

2011

Cold Spring Harbor Perspectives in Biology

392

336

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“…As shown in Figure 1a, various AGPAT2 mutations, including null, splice-site, frame-shift, insertion and deletion, have been found in several affected subjects. [5][6][7][8] The IVS4-2A4G mutation was found to recur in pedigrees of African origin and the chromosomes carrying it had the same haplotype for seven SNPs within and around AGPAT2, indicating that this mutation is of ancestral origin. 5 AGPAT2, a 278 amino-acid protein, catalyses an essential acylation reaction in the biosynthesis of all glycerophospholipids and TG in eukaryotes (Figure 1b).…”

Section: Cgl1 Locusmentioning

confidence: 99%

“…9,11 Our data reveal that AGPAT2 expression is at least two-fold higher than AGPAT1 in the normal human omental adipose tissue (Figure 1c). 5 Furthermore, AGPAT2 is expressed at lower level in the liver and much less in the skeletal muscle compared to adipose tissue. Glycerol-3-phosphate (G-3-P) is the initial substrate that is acylated at sn-1 position by the enzyme glycerol-3-phosphate acyltransferase (GPAT) to form 1-acylglycerol-3-phosphate or lysophosphatidic acid (LPA).…”

Section: Cgl1 Locusmentioning

confidence: 99%

“…(c) Expression patterns of AGPAT1 and AGPAT2 isoforms in human omental adipose tissue, liver and muscle. Amplified AGPATs were normalized to the signal generated from G3PDH and expressed as arbitrary units, details in Agarwal et al 5 (d) Schematic showing substrate specificities of AGPAT1 and 2. Using similar LPA, the two isoforms can produce different PAs.…”

Section: Cgl1 Locusmentioning

confidence: 99%

“…3 Using additional markers between D9S1826 and D9S1838 further refined the region. 5 Several genes expressed in the region, which could be involved in adipocyte differentiation, proliferation, apoptosis and triacylglycerol (TG) biosynthesis, were evaluated including 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2).…”

Section: Cgl1 Locusmentioning

confidence: 99%

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Genetic basis of congenital generalized lipodystrophy

2003

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Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by extreme lack of body fat and severe insulin resistance since birth. Recently, mutations have been reported in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2 or Seipin) genes in affected subjects from pedigrees linked to chromosomes 9q34 and 11q13, respectively. The AGPAT2 catalyses 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 to other isoforms suggests that the mutations might affect the adipose tissue the most. The function of BSCL2 remains unknown. Several CGL pedigrees reveal no mutation in either of the above genes and are not linked to these loci, suggesting additional genetic loci for CGL. Thus, several distinct mechanisms can lead to extreme lack of adipose tissue in humans and cause CGL.

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Lipodystrophies and Diabetes

Garg

Misra

2003

International Textbook of Diabetes Mellitus

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Lipodystrophies are heterogeneous disorders of adipose tissue, characterized by selective loss of body fat and a predisposition to develop insulin resistance, diabetes mellitus, hyperlipidemia, and hepatic steatosis. These disorders can be either genetic or acquired. The extent of fat loss can also vary from being localized or partial to generalized. Among the genetic lipodystrophies, congenital generalized lipodystrophy is caused by mutations in 1‐acylglycerol‐3‐phosphate O ‐acyltransferase 2 ( AGPAT2 ) and Berardinelli–Seip Congenital Lipodystrophy 2 ( BSCL2 ) genes and familial partial lipodystrophies by defects in lamin A/C ( LMNA ) and peroxisome proliferator‐activated receptor γ ( PPARG ) genes. Acquired generalized and partial lipodystrophies are likely to be autoimmune diseases. Lipodystrophy in HIV‐infected patients is mainly due to prolonged treatment with HIV‐1 protease inhibitors. Diabetes in patients with lipodystrophies may be caused by severe insulin resistance (hepatic and peripheral) and decrease in the insulin secretion due to pancreatic islet amyloidosis and β‐cell atrophy. Hyperglycemia is difficult to manage despite large doses of insulin but does not lead to ketosis. Recombinant human leptin has been reported to drastically improve hyperglycemia and hypertriglyceridemia in lipodystrophy patients with low serum leptin levels. It is hoped that our understanding of the pathogenesis of these disorders will contribute to a better understanding of adipocyte physiology, and of the molecular mechanisms of insulin resistance and eventually to better therapeutic options.

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AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34

Cited by 470 publications

References 15 publications

Not Just Fat: The Structure and Function of the Lipid Droplet

Not Just Fat: The Structure and Function of the Lipid Droplet

Genetic basis of congenital generalized lipodystrophy

Lipodystrophies and Diabetes

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