The Experts below are selected from a list of 108 Experts worldwide ranked by ideXlab platform
Abhimanyu Garg - One of the best experts on this subject based on the ideXlab platform.
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novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability
American Journal of Medical Genetics Part A, 2008Co-Authors: Vinaya Simha, Patricia A Aronin, Susan T. Iannaccone, Anil K Agarwal, Abhimanyu GargAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme paucity of adipose tissue from birth, and early onset of metabolic complications related to insulin resistance. Mutations in three genes, 1-acylglycerol 3-phosphate-O-Acyltransferase 2 (AGPAT2), Berardinelli Seip Congenital Lipodystrophy 2 (BSCL2), and Caveolin-1 (CAV1) are associated with the three subtypes of this disorder, CGL1, CGL2 and CGL3, respectively. We report two siblings of Hispanic origin who displayed characteristic features of CGL such as generalized loss of subcutaneous fat from birth, acanthosis nigricans, acromegaloid habitus, umbilical prominence, hepatosplenomegaly, hypoleptinemia, dyslipidemia, and insulin resistance. However, no disease causing variants were detected in the DNA sequence of AGPAT2, BSCL2 or CAV1 genes. Further, whole body magnetic resonance imaging (MRI) in the two siblings revealed marked loss of subcutaneous, intraabdominal and intrathoracic fat like in other patients with CGL, but preservation of bone marrow fat which is invariably lost in all patients with CGL1 and CGL2, but not in the patient reported with CGL3. They also had generalized muscle weakness during infancy and early childhood associated with a nearly fivefold increase in serum creatine kinase (CK) levels, but with normal muscle biopsy and electrophysiologic studies. Both patients were also found to have atlantoaxial dislocation requiring surgical intervention. Thus, this pedigree represents a novel subtype of CGL characterized by generalized loss of body fat but with preservation of bone marrow fat, congenital muscular weakness and cervical spine instability. The genetic basis of this novel subtype remains to be determined.
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phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the agpat2 or seipin genes
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Vinaya Simha, Abhimanyu GargAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive syndrome characterized by extreme paucity of adipose tissue since birth, acanthosis nigricans, severe insulin resistance, marked hypertriglyceridemia, and early-onset diabetes mellitus. 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). Whether the two subtypes have differences in body fat distribution has not been investigated. We, therefore, compared whole-body adipose tissue distribution by magnetic resonance imaging in 10 CGL patients, of whom seven (six females, one male) had CGL1 and three (two males, one female) had CGL2. Both subtypes had marked lack of metabolically active adipose tissue located at most sc, intermuscular, bone marrow, intraabdominal, and intrathoracic regions. Paucity of mechanical adipose tissue in t...
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agpat2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34
Nature Genetics, 2002Co-Authors: Anil K Agarwal, Elif Arioglu, Salome De Almeida, Nurullah Akkoc, Simeon I Taylor, Anne M Bowcock, Robert Barnes, Abhimanyu GargAbstract:Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. We report several different mutations of the gene (AGPAT2) encoding 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 in 20 affected individuals from 11 pedigrees of diverse ethnicities showing linkage to chromosome 9q34. The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. AGPAT2 mRNA is highly expressed in adipose tissue. We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes.
Anil K Agarwal - One of the best experts on this subject based on the ideXlab platform.
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novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability
American Journal of Medical Genetics Part A, 2008Co-Authors: Vinaya Simha, Patricia A Aronin, Susan T. Iannaccone, Anil K Agarwal, Abhimanyu GargAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme paucity of adipose tissue from birth, and early onset of metabolic complications related to insulin resistance. Mutations in three genes, 1-acylglycerol 3-phosphate-O-Acyltransferase 2 (AGPAT2), Berardinelli Seip Congenital Lipodystrophy 2 (BSCL2), and Caveolin-1 (CAV1) are associated with the three subtypes of this disorder, CGL1, CGL2 and CGL3, respectively. We report two siblings of Hispanic origin who displayed characteristic features of CGL such as generalized loss of subcutaneous fat from birth, acanthosis nigricans, acromegaloid habitus, umbilical prominence, hepatosplenomegaly, hypoleptinemia, dyslipidemia, and insulin resistance. However, no disease causing variants were detected in the DNA sequence of AGPAT2, BSCL2 or CAV1 genes. Further, whole body magnetic resonance imaging (MRI) in the two siblings revealed marked loss of subcutaneous, intraabdominal and intrathoracic fat like in other patients with CGL, but preservation of bone marrow fat which is invariably lost in all patients with CGL1 and CGL2, but not in the patient reported with CGL3. They also had generalized muscle weakness during infancy and early childhood associated with a nearly fivefold increase in serum creatine kinase (CK) levels, but with normal muscle biopsy and electrophysiologic studies. Both patients were also found to have atlantoaxial dislocation requiring surgical intervention. Thus, this pedigree represents a novel subtype of CGL characterized by generalized loss of body fat but with preservation of bone marrow fat, congenital muscular weakness and cervical spine instability. The genetic basis of this novel subtype remains to be determined.
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phenotypic and genetic heterogeneity in congenital generalized lipodystrophy
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Anil K Agarwal, Vinaya Simha, Elif A Oral, Stephanie Ann Moran, Phillip Gorden, Stephen Orahilly, Zohra Zaidi, Figen Gurakan, Silva A Arslanian, Aharon KlarAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity. (J Clin Endocrinol Metab 88: 4840 – 4847, 2003)
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phenotypic and genetic heterogeneity in congenital generalized lipodystrophy
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Anil K Agarwal, Vinaya Simha, Elif A Oral, Stephanie Ann Moran, Phillip Gorden, Stephen Orahilly, Zohra Zaidi, Figen Gurakan, Silva A Arslanian, Aharon KlarAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.
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agpat2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34
Nature Genetics, 2002Co-Authors: Anil K Agarwal, Elif Arioglu, Salome De Almeida, Nurullah Akkoc, Simeon I Taylor, Anne M Bowcock, Robert Barnes, Abhimanyu GargAbstract:Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. We report several different mutations of the gene (AGPAT2) encoding 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 in 20 affected individuals from 11 pedigrees of diverse ethnicities showing linkage to chromosome 9q34. The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. AGPAT2 mRNA is highly expressed in adipose tissue. We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes.
Takao Shimizu - One of the best experts on this subject based on the ideXlab platform.
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Generation of membrane diversity by lysophospholipid acyltransferases.
Journal of biochemistry, 2013Co-Authors: Daisuke Hishikawa, Miki Eto, Takeshi Harayama, Takao ShimizuAbstract:Glycerophospholipids are main components of cellular membranes and have numerous structural and functional roles to regulate cellular functions. Polyunsaturated fatty acids, such as arachidonic acid and eicosapentaenoic acid, are mainly located at the sn-2, but not the sn-1 position of glycerophospholipids in an asymmetrical manner and the fatty acid compositions at both the sn-1 and sn-2 positions differ in various cell types and tissues. Asymmetry and diversity of membrane glycerophospholipids are generated in the remodelling pathway (Lands' cycle), which are conducted by the concerted actions of phospholipases A2 (PLA2s) and lysophospholipid acyltransferases (LPLATs). The Lands' cycle was first reported in the 1950s. While PLA2s have been well characterized, little is known about the LPLATs. Recently, several laboratories, including ours, isolated LPLATs that function in the Lands' cycle from the 1-Acylglycerol-3-Phosphate O-Acyltransferase family and the membrane bound O-Acyltransferases family. In this review, we summarize recent studies on cloning and characterization of LPLATs that contribute to membrane asymmetry and diversity.
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recent progress on acyl coa lysophospholipid acyltransferase research
Journal of Lipid Research, 2009Co-Authors: Hideo Shindou, Takeshi Harayama, Daisuke Hishikawa, Koichi Yuki, Takao ShimizuAbstract:Cells of all organisms are enclosed by a plasma membrane containing bipolar lipids, cholesterol, and proteins. Cellular membranes contain several classes of glycerophospholipids, which have numerous structural and functional roles in cells. Polyunsaturated fatty acids including arachidonic acid and eicosapentaenoic acid are usually located at the sn-2 position, but not the sn-1 position, of glycerophospholipids in an asymmetrical manner. Glycerophospholipids are first formed by the de novo pathway (Kennedy pathway) using acyl-CoAs as donors. Subsequently, in the remodeling pathway (Lands' cycle), cycles of deacylation and reacylation of glycerophospholipids modify the fatty acid composition to generate mature membrane with asymmetry and diversity. Both pathways were proposed in the 1950s. Whereas the enzymes involved in the Kennedy pathway have been well characterized, little is known about the enzymes involved in the Lands' cycle. Recently, several laboratories, including ours, have identified enzymes working in the Lands' cycle from the 1-Acylglycerol-3-Phosphate O-Acyltransferase (AGPAT) family, and also from the membrane bound O-Acyltransferases (MBOAT) family. These discoveries have prompted a robust surge of research in this field. In this review, we focus on the cloning and characterization of lysophospholipid acyltransferases (LPLATs), which contribute to membrane asymmetry and diversity.
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Acyl-CoA:lysophospholipid acyltransferases.
The Journal of biological chemistry, 2008Co-Authors: Takao ShimizuAbstract:Cell membranes contain several classes of glycerophospholipids, which have numerous structural and functional roles in the cells. Polyunsaturated fatty acids, including arachidonic acid and eicosapentaenoic acid, are located at the sn-2 (but not sn-1)-position of glycerophospholipids in an asymmetrical manner. Using acyl-CoAs as donors, glycerophospholipids are formed by a de novo pathway (Kennedy pathway) and modified by a remodeling pathway (Lands' cycle) to generate membrane asymmetry and diversity. Both pathways were reported in the 1950s. Whereas enzymes involved in the Kennedy pathway have been well characterized, including enzymes in the 1-Acylglycerol-3-Phosphate O-Acyltransferase family, little is known about enzymes involved in the Lands' cycle. Recently, several laboratories, including ours, isolated enzymes working in the remodeling pathway. These enzymes were discovered not only in the 1-Acylglycerol-3-Phosphate O-Acyltransferase family but also in the membrane-bound O-Acyltransferase family. In this review, we summarize recent studies on cloning and characterization of lysophospholipid acyltransferases that contribute to membrane asymmetry and diversity.
Vinaya Simha - One of the best experts on this subject based on the ideXlab platform.
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novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability
American Journal of Medical Genetics Part A, 2008Co-Authors: Vinaya Simha, Patricia A Aronin, Susan T. Iannaccone, Anil K Agarwal, Abhimanyu GargAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme paucity of adipose tissue from birth, and early onset of metabolic complications related to insulin resistance. Mutations in three genes, 1-acylglycerol 3-phosphate-O-Acyltransferase 2 (AGPAT2), Berardinelli Seip Congenital Lipodystrophy 2 (BSCL2), and Caveolin-1 (CAV1) are associated with the three subtypes of this disorder, CGL1, CGL2 and CGL3, respectively. We report two siblings of Hispanic origin who displayed characteristic features of CGL such as generalized loss of subcutaneous fat from birth, acanthosis nigricans, acromegaloid habitus, umbilical prominence, hepatosplenomegaly, hypoleptinemia, dyslipidemia, and insulin resistance. However, no disease causing variants were detected in the DNA sequence of AGPAT2, BSCL2 or CAV1 genes. Further, whole body magnetic resonance imaging (MRI) in the two siblings revealed marked loss of subcutaneous, intraabdominal and intrathoracic fat like in other patients with CGL, but preservation of bone marrow fat which is invariably lost in all patients with CGL1 and CGL2, but not in the patient reported with CGL3. They also had generalized muscle weakness during infancy and early childhood associated with a nearly fivefold increase in serum creatine kinase (CK) levels, but with normal muscle biopsy and electrophysiologic studies. Both patients were also found to have atlantoaxial dislocation requiring surgical intervention. Thus, this pedigree represents a novel subtype of CGL characterized by generalized loss of body fat but with preservation of bone marrow fat, congenital muscular weakness and cervical spine instability. The genetic basis of this novel subtype remains to be determined.
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phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the agpat2 or seipin genes
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Vinaya Simha, Abhimanyu GargAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive syndrome characterized by extreme paucity of adipose tissue since birth, acanthosis nigricans, severe insulin resistance, marked hypertriglyceridemia, and early-onset diabetes mellitus. 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). Whether the two subtypes have differences in body fat distribution has not been investigated. We, therefore, compared whole-body adipose tissue distribution by magnetic resonance imaging in 10 CGL patients, of whom seven (six females, one male) had CGL1 and three (two males, one female) had CGL2. Both subtypes had marked lack of metabolically active adipose tissue located at most sc, intermuscular, bone marrow, intraabdominal, and intrathoracic regions. Paucity of mechanical adipose tissue in t...
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phenotypic and genetic heterogeneity in congenital generalized lipodystrophy
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Anil K Agarwal, Vinaya Simha, Elif A Oral, Stephanie Ann Moran, Phillip Gorden, Stephen Orahilly, Zohra Zaidi, Figen Gurakan, Silva A Arslanian, Aharon KlarAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity. (J Clin Endocrinol Metab 88: 4840 – 4847, 2003)
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phenotypic and genetic heterogeneity in congenital generalized lipodystrophy
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Anil K Agarwal, Vinaya Simha, Elif A Oral, Stephanie Ann Moran, Phillip Gorden, Stephen Orahilly, Zohra Zaidi, Figen Gurakan, Silva A Arslanian, Aharon KlarAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.
Aharon Klar - One of the best experts on this subject based on the ideXlab platform.
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phenotypic and genetic heterogeneity in congenital generalized lipodystrophy
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Anil K Agarwal, Vinaya Simha, Elif A Oral, Stephanie Ann Moran, Phillip Gorden, Stephen Orahilly, Zohra Zaidi, Figen Gurakan, Silva A Arslanian, Aharon KlarAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity. (J Clin Endocrinol Metab 88: 4840 – 4847, 2003)
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phenotypic and genetic heterogeneity in congenital generalized lipodystrophy
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Anil K Agarwal, Vinaya Simha, Elif A Oral, Stephanie Ann Moran, Phillip Gorden, Stephen Orahilly, Zohra Zaidi, Figen Gurakan, Silva A Arslanian, Aharon KlarAbstract:Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.
