Mutations in<i>Gng3lg</i>and<i>AGPAT2</i>in Berardinelli-Seip Congenital Lipodystrophy and Brunzell Syndrome: Phenotype Variability Suggests Important Modifier Effects

Fu, Mao; Kazlauskaite, Rasa; Baracho, Maria de Fátima Paiva; Santos, Maria Goretti do Nascimento; Brandão-Neto, José; Villares, S M; Celi, Francesco S.; Wajchenberg, B. L.; Shuldiner, Alan R.

doi:10.1210/jc.2003-030485

Cited by 52 publications

(52 citation statements)

References 18 publications

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“…However, CGL2 appeared to have a higher incidence of premature death than CGL1 and a pattern of lipodystrophy that was distinguished by earlier onset and greater severity (21). Also, subjects with CGL2 had a significantly higher prevalence of intellectual impairment than those with CGL1 or CGL with no detected molecular basis (21,22). In addition, cystic angiomatosis with progressive incapacitating bone involvement was associated with mutations in AGPAT2 but not seipin (22), clarifying that a syndrome composed of CGL with systemic cystic angiomatosis, sometimes called Brunzell syndrome (23), was actually a subtype of CGL1.…”

Section: Cgl1 and Cgl2 Phenotypes Considered In The Light Of Moleculamentioning

confidence: 97%

“…Also, subjects with CGL2 had a significantly higher prevalence of intellectual impairment than those with CGL1 or CGL with no detected molecular basis (21,22). In addition, cystic angiomatosis with progressive incapacitating bone involvement was associated with mutations in AGPAT2 but not seipin (22), clarifying that a syndrome composed of CGL with systemic cystic angiomatosis, sometimes called Brunzell syndrome (23), was actually a subtype of CGL1. Cardiomyopathy appears to be more severe in CGL2 (11).…”

Section: Cgl1 and Cgl2 Phenotypes Considered In The Light Of Moleculamentioning

confidence: 97%

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Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism

Hegele

Joy

Al-Attar

et al. 2007

Journal of Lipid Research

127

103

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The lipodystrophies are characterized by loss of adipose tissue in some anatomical sites, frequently with fat accumulation in nonatrophic depots and ectopic sites such as liver and muscle. Molecularly characterized forms include Dunnigan-type familial partial lipodystrophy (FPLD), partial lipodystrophy with mandibuloacral dysplasia (MAD), Berardinelli-Seip congenital generalized lipodystrophy (CGL), and some cases with Barraquer-Simons acquired partial lipodystrophy (APL). The associated mutant gene products include 1) nuclear lamin A in FPLD type 2 and MAD type A; 2) nuclear lamin B2 in APL; 3) nuclear hormone receptor peroxisome proliferator-activated receptor g in FPLD type 3; 4 ) lipid biosynthetic enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 in CGL type 1; 5 ) integral endoplasmic reticulum membrane protein seipin in CGL type 2; and 6 ) metalloproteinase ZMPSTE24 in MAD type B. An unresolved question is whether metabolic disturbances are secondary to adipose repartitioning or result from a direct effect of the mutant gene product. Careful analysis of clinical, biochemical, and imaging phenotypes, using an approach called "phenomics," reveals differences between genetically stratified subtypes that can be used to guide basic experiments and to improve our understanding of common clinical entities, such as metabolic syndrome or the partial lipodystrophy syndrome associated with human immunodeficiency virus infection.-Hegele, R. A., T. R. Joy, S. A. Al-Attar, and B. K. Rutt. Lipodystrophies: windows on adipose biology and metabolism. J. Lipid Res.

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Section: Cgl1 and Cgl2 Phenotypes Considered In The Light Of Moleculamentioning

confidence: 97%

Section: Cgl1 and Cgl2 Phenotypes Considered In The Light Of Moleculamentioning

confidence: 97%

Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism

Hegele

Joy

Al-Attar

et al. 2007

Journal of Lipid Research

127

103

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“…27 Several genes have been identified that can cause total lipodystrophy, including 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), which converts 1-acyl glycerol phosphate to 1,2 diacylglycerol phosphate (phosphaditic acid); without AGPAT2, TG synthesis and adipogenesis are disrupted. 28,29 A second gene, called seipin, has no known function, and the way in which it causes lipodystrophy is unknown. 29 There are partial lipodystrophies, some of which have been associated with mutations in the gene for lamins A and C (LMNA), and in the PPAR␥ gene.…”

Section: Insulin-resistant Adipose Tissue and Dysregulation Of Lipid mentioning

confidence: 99%

“…28,29 A second gene, called seipin, has no known function, and the way in which it causes lipodystrophy is unknown. 29 There are partial lipodystrophies, some of which have been associated with mutations in the gene for lamins A and C (LMNA), and in the PPAR␥ gene. 30 In total lipodystrophy, plasma FA levels are very high, and TG accumulates in muscle, liver, islet cells, and plasma, resulting in insulin resistance, hypertriglyceridemia, and defective insulin secretion with diabetes.…”

Section: Insulin-resistant Adipose Tissue and Dysregulation Of Lipid mentioning

confidence: 99%

Adipocyte Signaling and Lipid Homeostasis

Ginsberg

2005

Circulation Research

292

122

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Abstract-For many years adipose tissue was viewed as the site where excess energy was stored, in the form of triglycerides (TGs), and where that energy, when needed elsewhere in the body, was released in the form of fatty acids (FAs). Recently, it has become clear that when the regulation of the storage and release of energy by adipose tissue is impaired, plasma FA levels become elevated and excessive metabolism of FA, including storage of TGs, occurs in nonadipose tissues. Most recently, work by several laboratories has made it clear that in addition to FA, adipose tissue communicates with the rest of the body by synthesizing and releasing a host of secreted molecules, collectively designated as adipokines. Several recent reviews have described how these molecules, along with FA, significantly effect total body glucose metabolism and insulin sensitivity. Relatively little attention has been paid to the effects of adipokines on lipid metabolism. In this review, we will describe, in detail, the effects of molecules secreted by adipose tissue, including FA, leptin, adiponectin, resistin, TNF-␣, IL-6, and apolipoproteins, on lipid homeostasis in several nonadipose tissues, including liver, skeletal muscle, and pancreatic ␤ cells. Key Words: lipids Ⅲ fatty acids Ⅲ adipose tissue Ⅲ insulin resistance Ⅲ cytokines F or many years adipose tissue was viewed as playing a passive role in total body lipid and energy homeostasis. Adipose tissue was the site where excess energy was stored, in the form of triglycerides (TGs), and where that energy, when needed elsewhere in the body, was released in the form of fatty acid (FA). Work by numerous laboratories during the second half of the 20th century made it clear that under normal conditions, the storage and release of TG and FA, respectively, are both coordinated and tightly regulated so that lipid fuels are stored during the immediate postprandial periods and released during periods of fasting. The biochemistry of key molecules critical to coordinating storage and release of energy, such as lipoprotein lipase (LPL) and hormone sensitive lipase (HSL), was characterized in detail during that period. More recently, it has become clear that when the regulation of storage and release of energy by adipose tissue is impaired, particularly when release of FA becomes dissociated from energy requirements in other organs and tissues, plasma FA levels become elevated and excessive metabolism of FA, including storage of TG, occurs in nonadipose tissues.Our initial understanding of how fat tissue communicates with other tissues and organs to integrate total body lipid homeostasis was limited to the effects of circulating FA on hepatic lipid and glucose metabolism. During the last 15 years, however, it has become clear that adipose tissue- derived FA can affect lipid metabolism in several tissues, including muscle and pancreatic ␤ cells. The expanded view of ectopic metabolism or accumulation of FA or TG is that it causes dysfunction, or lipotoxicity, in these organs and tissues. Most recen...

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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: 97%

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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Mutations inGng3lgandAGPAT2in Berardinelli-Seip Congenital Lipodystrophy and Brunzell Syndrome: Phenotype Variability Suggests Important Modifier Effects

Cited by 52 publications

References 18 publications

Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism

Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism

Adipocyte Signaling and Lipid Homeostasis

Genetic basis of congenital generalized lipodystrophy

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