| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Internal Medicine (A.K.A., V.S., A.G.), Division of Nutrition and Metabolic Diseases and Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Internal Medicine (E.A.O.), University of Michigan, Ann Arbor, Michigan 48109; Diabetes Branch (S.A.M., P.G.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892; Department of Medicine (S.O.), Cambridge Medical School, Addenbrooke’s Hospital, United Kingdom CB2 2QR; Department of Dermatology (Z.Z.), Jinnah Postgraduate Medical Center, Karachi, Pakistan 75510; Department of Pediatric Gastroenterology (F.G.), Hacettepe University Medical Faculty, Ankara 06100, Turkey; Department of Pediatrics (S.A.A.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Pediatrics (A.K.), Bikur Cholim Hospital, Jerusalem 91004, Israel; Department of Pediatrics (A.R.), Children’s Hospital, Harvard University, Boston, Massachusetts 02115; Department of Pediatrics (N.H.W.), Washington University School of Medicine, St. Louis, Missouri 63110; Department of Pediatrics (L.B.), University Children’s Hospital, D-53113 Bonn, Germany; Department of Medicine (K.H.), Charles R. Drew University, Los Angeles, California 90059; Department of Endocrinology (K.K.), Mayo Clinic, Rochester, Minnesota 55905; Division of Endocrinology (S.B.P.), Medical University of South Carolina, Charleston, South Carolina 29403; and Department of Pediatrics (L.A.-G.), The United Arab Emirates University Faculty of Medicine and Health Services, Al Ain, United Arab Emirates
Address all correspondence and requests for reprints to: Dr. Abhimanyu Garg, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: abhimanyu.garg{at}utsouthwestern.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Recent studies have revealed two loci for CGL, and mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) were reported in pedigrees linked to chromosome 9q34 (3), and in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene in pedigrees linked to chromosome 11q13 (13). Whether there are additional loci for CGL remains to be established. Furthermore, the phenotypic differences between CGL patients with AGPAT2 or BSCL2 mutations or those without mutations in either of these two genes have not been well characterized (3, 4). Therefore, we conducted mutational analysis of 45 pedigrees with CGL, of various ethnicities ascertained from all over the world, for mutations in AGPAT2 and BSCL2 genes and linkage to these loci, and evaluated the phenotypic differences between the various subtypes of CGL.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A total of 45 pedigrees have been ascertained by us from all over the world. Pedigrees of the 11 CGL families with AGPAT2 mutations were recently published by us (3). The remaining 34 pedigrees are shown in Figs. 1–3
. The protocol was approved by the appropriate Institutional Review Boards, and all subjects gave informed consent. The phenotype was classified as affected or unaffected on the basis of history, physical examination, review of medical records, responses to a written questionnaire, and inspection of photographs where available. Generalized lack of body fat since birth was considered the essential criterion for diagnosis. Additional supportive criteria included the presence of acanthosis nigricans, diabetes mellitus, hypertriglyceridemia, or low serum high-density lipoprotein cholesterol levels. In some patients, generalized lack of body fat on whole body magnetic resonance imaging provided confirmation of the diagnosis. Patients with acquired generalized lipodystrophy were excluded on the basis of their normal appearance at birth with gradual onset of loss of fat subsequently (14), whereas those with Wiedemann-Rautenstrauch syndrome were excluded based on the presence of supragluteal fat pads and other somatic anomalies (2).
|
|
|
Blood samples were also obtained from 50 unaffected subjects (25 each of European and African origin) to screen for mutations in the AGPAT2 gene.
Mutational analysis
Lymphoblastoid cell lines were established by Epstein-Barr virus transformation of peripheral blood lymphocytes, and genomic DNA was isolated from these cells or from buffy coat using DNAzol (Life Technologies, Inc., Rockville, MD) according to the manufacturer’s protocol. The coding regions and the splice site junctions of the AGPAT2 and BSCL2 genes were amplified by using gene-specific primers (available on request). PCR was assembled as described earlier (3). The PCR product was purified to remove primers and deoxynucleotide triphosphate and sequenced using ABI Prism 3100 (Applied Biosystems, Foster City, CA).
Linkage analysis
To study linkage to the AGPAT2 and BSCL2 loci, we chose the dinucleotide repeat markers D9S1826, D9S158, D9S905 and D9S1838 flanking the AGPAT2 gene in the 9q34 region, and D11S2006, D11S2016, D11S913 and D11S2363 flanking the BSCL2 gene in the 11q13 region. The PCR products were analyzed on ABI 377, and linkage analysis was performed manually.
Transcript analysis
To detect any mutations in the noncoding regions (introns, proximal regulatory regions, and 3' untranslated regions) of the AGPAT2 and BSCL2 genes, we performed transcript analysis on patients whose transformed lymphocytes were available. Transformed lymphoblasts of the affected subjects were spun down to remove the culture medium and lysed with RNA-Stat-60 (Tel-Test, Friendswood, TX). Total RNA was extracted according to the manufacturer’s protocol. Approximately 5 µl (2.5–5 µg) of total RNA were used for the reverse-transcriptase reaction using Thermoscript RT-PCR system (Life Technologies, Inc.) in a 20-µl reaction volume according to the manufacturer’s protocol with minor modification. Briefly, DNase I was added to the total RNA to remove residual genomic DNA and heat-inactivated at 65 C for 10 min. The reverse transcriptase reaction was carried out for 50 min at 50 C, followed by inactivation at 85 C for 5 min. Residual RNA was removed by treating the reaction with 2 U of RNase H for 20 min at 37 C. The cDNA was used for PCR using primer pair AGPAT2_F and AGPAT_6Ra, spanning the entire coding region of both the genes. PCR conditions were the same as mentioned above for exon amplification.
Biochemical analysis
Serum leptin was measured using a commercial RIA for human leptin (Linco Research, Inc., St. Charles, MO). Serum glucose and triglyceride levels were determined according to standard methods using automated equipment (Beckman Instruments, Fullerton, CA).
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Of the 45 pedigrees studied, 26 harbored mutations in the AGPAT2 gene, 11 in the BSCL2 gene, and eight in neither of these two genes. The mutations found in AGPAT2 and BSCL2 in the affected subjects segregated in their parents and unaffected siblings in accordance with Mendelian autosomal recessive inheritance.
Mutations in the AGPAT2 gene
We found mutations in the AGPAT2 gene in affected patients from a total of 26 pedigrees, including 11 pedigrees that have been reported previously (3). In affected individuals from families CG4800, 5000, 5100, 5300, 5400, 5500, 6700, 8100, and 8200 of African origin, previously described IVS4–2A>G mutation (Table 1 and Fig. 1A
) was detected. The pedigrees CG4800, 5300, 5400, 5500, 6700, 8100 and 8200 had the homozygous IVS4-2A>G mutation. Affected subjects from pedigrees CG5000 and 5100 were compound heterozygotes for novel mutations, 570C>A, and a splice site mutation, IVS3 + 1G>A, respectively. Interestingly, the affected subjects from the Hispanic pedigree CG9500 also had the same (IVS4–2A>G) homozygous mutation. We had reported earlier that the IVS4–2A>G mutation in subjects of African origin had a common ancestral origin and that the chromosome carrying the mutation in these pedigrees shared a common haplotype spanning 33 kb around the mutation, including dinucleotide repeat markers and single nucleotide polymorphisms (SNPs). We therefore compared the haplotype generated from the known SNPs within the AGPAT2 gene in the pedigree CG9500 with the previously reported haplotype for the African pedigrees (3). Indeed the IVS4–2A>G mutation in CG9500 was associated with a different haplotype than that noted in the African pedigrees (Table 2), indicating that it originated by a separate mutational event. Although there was no evidence of consanguinity, the chromosome carrying the mutation in both the parents shared the same haplotype.
|
|
Sequencing of all exons of the AGPAT2 gene in 50 unaffected individuals revealed no mutations.
Mutations in the BSCL2 gene
Mutations in the BSCL2 gene were found in affected patients from 11 pedigrees (Table 3 and Fig. 1B). In the pedigrees CG 4100, 4700, 6800, and 6900, which were of Lebanese descent, we observed a homozygous five-nucleotide deletion in exon 4 (659delGTATC) leading to frameshift and truncated protein, F105fsX111. Magre et al. (13) also observed the same mutation in CGL pedigrees ascertained from Lebanon. An affected subject from a Portuguese pedigree (CG3800) had a homozygous insertion of a nucleotide, 669insA in exon 4, resulting in a frameshift and truncated protein, F108fsX113. We detected a novel mutation, a dinucleotide insertion, 500insTT, in exon 2 in CG1000 pedigree from Pakistan, which leads to frameshift and premature stop, F53fsX93. The affected subject from pedigree CG1100 of Chinese descent had a heterozygous single nucleotide, guanine insertion at position 1126 in exon 7 (1126insG), resulting in frameshift and a truncated protein of 283 residues, G271fsX283. We were unable to find another mutation in the coding region, splice site junctions, as well as in the 1.5-kb 5' proximal region of the BSCL2 gene in this subject. A novel homozygous splice site mutation IVS6-3C>G was observed in a Turkish pedigree (CG100), whereas affected patients from CG1300, a pedigree of Chinese origin showed a homozygous IVS6–2A>G mutation. On analysis of the transcripts, we found that both of these mutations resulted in a frameshift and a truncated protein of 288 residues, F224fsX288. A novel, homozygous null mutation L227X was detected in the affected subject from pedigree CG1200. Affected individuals from CG2800, of British origin, were found to be compound heterozygotes with a splice site mutation IVS6+5G>A and a 537delCinsGGA mutation, both of which resulted in a frameshift and truncated proteins of 225 and 91 residues, respectively.
|
Pedigrees lacking mutations in AGPAT2 or BSCL2 genes (other CGL types)
We identified eight CGL pedigrees (Fig. 3) in which the affected patients showed no substantial alterations in the coding regions of the AGPAT2 and BSCL2 genes by direct sequencing. Of these eight pedigrees, three (CG3100, 5600, and 7100) had enough power for linkage analysis. We further analyzed these pedigrees using polymorphic microsatellite markers in the 9q34 and 11q13 regions flanking the AGPAT2 and BSCL2 genes, respectively. Pedigrees 5600 and 7100 showed linkage to 9q34 region, but transcript analysis did not reveal any mutation in AGPAT2 gene. Pedigree CG3100 showed linkage to 11q13, and in CG5600, linkage data were inconclusive for this region. However, the transcript analysis of BSCL2 was normal in affected individuals from the CG3100 and CG5600 pedigrees. Of the remaining five pedigrees, which were not included in the linkage analysis due to lack of power, lymphoblastoid cell lines were only available in affected subjects from three pedigrees (CG 300, 4200, and 4300). Transcript analysis in affected subjects from these pedigrees was normal for BSCL2 and AGPAT2 genes (Table 4). Linkage and transcript analysis could not be performed in pedigrees CG1400 and CG4900.
|
Affected individuals from all 45 pedigrees had extreme paucity of sc adipose tissue from birth and markedly low serum leptin levels. Other characteristic features of CGL like acanthosis nigricans and umbilical prominence were also noted in almost all subjects. We noted a higher proportion of female subjects with AGPAT2 mutations (Table 5). There was a uniformly high prevalence of diabetes mellitus and hypertriglyceridemia in all of the CGL subtypes. However, patients with BSCL2 mutation had an earlier onset of diabetes at a median age of 10 yr, compared with those with AGPAT2 mutation who had onset of diabetes at a median age of 12.5 yr (P = 0.04). Although half of the patients with BSCL2 mutations were documented to have mental retardation, none with AGPAT2 mutations were noted to have impaired mental functions (P < 0.0001). The prevalence of cardiomyopathy was also over three times higher in those with BSCL2 mutations compared with those with AGPAT2 mutations, and approached statistical significance (P = 0.057). Serum leptin levels were lower in patients with BSCL2 mutations compared with those with AGPAT2 mutations. On gender-specific comparisons, females with BSCL2 mutation had significantly lower serum leptin levels than those with AGPAT2 mutation (0.48 ± 0.32 vs. 1.08 ± 0.78 ng/ml, respectively; P < 0.05), whereas serum leptin levels in males with AGPAT2 and BSCL2 mutation were comparable (0.36 ± 0.22 and 0.56 ± 0.43 ng/ml, respectively; P = 0.3).
|
Skeletal survey revealed that lytic bone lesions in the appendicular skeleton were almost exclusively limited to affected adult subjects with the AGPAT2 mutations. We had previously reported focal osteolytic lesions in long bones such as the femur, tibia, and humerus in affected subjects from pedigrees CG800 and CG900 (9) who have mutations in AGPAT2 (3). We found similar lesions in affected individuals from pedigrees CG400, 600, and 8200, all with AGPAT2 mutations. Skeletal surveys in affected subjects CG1300.3, 1300.5, 4700.12, and 6800.3, who have mutations in BSCL2, were essentially normal except for small lytic lesions in the humerus in patient CG4700.12.
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In one of the Hispanic pedigrees, we observed the homozygous mutation IVS4–2A>G on a haplotype different from that observed in the pedigrees of African origin. This suggests that this mutation may have occurred as a separate event. The occurrence of two homozygous mutations in the affected subjects from Buenos Aires, Argentina (CG4400 and CG6000), raises the question about which of the two mutations is likely to be disease causing. The Serine residue at position 100 in AGPAT2 lies within the conserved acyltransferase motif NHX4D (N, Asn; H, His; X, any amino acid; D, Asp) and may influence the enzymatic activity (Fig. 1C). However, the alignment of this motif in all the known human AGPATs reveals that this amino acid is not conserved between the different isoforms of AGPAT, although it is preserved in isoforms 1, 2, and 5 (Fig. 1C). Blast search, however, does reveal that this residue is conserved in known AGPAT2s across various species. Thus, the role of Serine 100 residue is uncertain; nevertheless, this mutation can influence the kinetic properties of the enzyme. On the other hand, the splice site mutation, IVS3–1G>C, is likely to skip exon 4 and thus cause an inactive truncated protein because exon 4 contains the EGTR (E, Glu; G, Gly; T, Thr; R, Arg) motif involved in catalytic activity of the enzyme. It is therefore likely that IVS3–1G>C is the disease-causing mutation. Interestingly, both families shared the same haplotype consisting of similar intragenic SNPs.
As regards the BSCL2 gene, the Lebanese and Norwegian mutations have been shown to be of ancestral origin, and our data in four Lebanese pedigrees further supports the previous findings. In addition, we report five novel mutations in the BSCL2 gene. Because all of these variants found by us are predicted to cause severe alteration of the predicted protein sequence, these are highly likely to be disease-causing mutations. The affected subject from pedigree CG1100 revealed only one heterozygous mutation in BSCL2. We were unable to locate the second BSCL2 mutation or any mutations in the AGPAT2 gene in this patient.
Among the 45 pedigrees we screened for AGPAT2 or BSCL2 mutations, eight affected pedigrees did not have any substantial alterations in either of these two genes. Patients who showed linkage to polymorphic microsatellite markers in either the 9q34 and 11q13 regions had normal transcript analysis of the AGPAT2 and BSCL2 genes. Our observations that some patients with CGL do not have mutations in either AGPAT2 or BSCL2 suggest additional genetic loci for CGL. Affected individuals from one of these pedigrees (CG7100) also had congenital myopathy. The high prevalence of cardiomyopathy in affected subjects from four pedigrees in this group is also interesting. It is likely that the genetic defect in these patients affects the development of both adipocytes and myocytes. Heathcote et al. (17) also reported two Omanese families with CGL who did not map to either the 9q34 or the 11q13 loci. However, affected patients from these pedigrees seem to have a different phenotype than that observed in typical patients with CGL, such as the presence of infantile pyloric stenosis and percussion myoedema. Furthermore, affected subjects from these pedigrees did not have diabetes or hyperinsulinemia.
Although patients with both AGPAT2 and BSCL2 mutations have similar metabolic abnormalities, there were many phenotypic differences between the two patient subgroups. We found a high preponderance of females to males among patients with AGPAT2 mutations but not in the other subtypes. Whether this reflects a sampling bias, or is due to the less severe fat loss in patients with AGPAT2 mutations that may cause the diagnosis to be missed in many males is not clear. We noticed significantly lower leptin levels in patients with BSCL2 mutation compared with AGPAT2 mutation, which may reflect more severe fat loss. We have noted that BSCL2 patients have loss of fat from their palms and soles, and from other areas where predominantly mechanical adipose tissue is present, whereas this is well preserved in patients with AGPAT2 mutation (18). However, in the present study, patients with BSCL2 mutations were younger, which could also account for their lower leptin levels. Other phenotypic differences between the two groups include the higher prevalence of mental retardation and cardiomyopathy in patients with BSCL2 mutation and the presence of lytic lesions in the appendicular skeleton in patients with AGPAT2 mutation. Van Maldergem et al. (4) also reported significantly higher prevalence of mental retardation in patients with BSCL2 mutations. It seems that high expression of BSCL2 in the brain may be related to increased prevalence of mental retardation in CGL patients with BSCL2 mutations.
AGPAT2 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 (19). High expression of AGPAT2 mRNA in adipose tissue compared with other isoforms suggests that the mutations might affect the adipose tissue the most (3). 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 (20).
The mechanisms by which BSCL2 mutations cause lipodystrophy, however, still remain unclear. Based on high expression of BSCL2 mRNA in the brain, a primary defect in hypothalamic-pituitary axis has been suggested to cause lipodystrophy (13). However, a recent semiquantitative RT-PCR of BSCL2 in our laboratory revealed twice as much expression in the human omental adipose tissue compared with liver, whereas skeletal muscle expression was very poor (21). Thus, besides a central nervous system defect, a primary abnormality in adipose tissue could cause lipodystrophy in patients with BSCL2 mutations.
It is quite likely that mutations in additional isoforms of AGPATs, as well as in the other enzymes of the pathway, such as glycerol-3-phosphate acyltransferases, phosphatidic acid phosphatases, and diacylglycerol acyltransferases may also cause CGL. Both mitochondrial glycerol-3-phosphate acyltransferase and the two microsomal isoforms of diacylglycerol acyltransferase are known to be highly expressed in the adipose tissue (20, 22, 23) and remain candidate genes for CGL patients without AGPAT2 or BSCL2 mutations.
In summary, CGL is caused by mutations in BSCL2, AGPAT2, and other as yet unmapped genes. This genetic heterogeneity is also accompanied by phenotypic heterogeneity.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
A.K.A. and V.S. contributed equally to this work.
Abbreviations: AGPAT2, 1-Acylglycerol-3-phosphate O-acyltransferase 2; BSCL2, Berardinelli-Seip congenital lipodystrophy 2; CGL, congenital generalized lipodystrophy; SNP, single nucleotide polymorphism.
Received May 16, 2003.
Accepted July 7, 2003.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  K. Takeuchi and K. Reue Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis Am J Physiol Endocrinol Metab, June 1, 2009; 296(6): E1195 - E1209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ito and N. Suzuki Seipinopathy: a novel endoplasmic reticulum stress-associated disease Brain, January 1, 2009; 132(1): 8 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Ferns, V Keti, and B Griffin Investigation and management of hypertriglyceridaemia J. Clin. Pathol., November 1, 2008; 61(11): 1174 - 1183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. Payne, N. Grimsey, A. Tuthill, S. Virtue, S. L. Gray, E. Dalla Nora, R. K. Semple, S. O'Rahilly, and J. J. Rochford The Human Lipodystrophy Gene BSCL2/Seipin May Be Essential for Normal Adipocyte Differentiation Diabetes, August 1, 2008; 57(8): 2055 - 2060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Garg and A. K. Agarwal Caveolin-1: A New Locus for Human Lipodystrophy J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1183 - 1185. [Full Text] [PDF]
|
|
|
|
|
|
C. A. Kim, M. Delepine, E. Boutet, H. El Mourabit, S. Le Lay, M. Meier, M. Nemani, E. Bridel, C. C. Leite, D. R. Bertola, et al. Association of a Homozygous Nonsense Caveolin-1 Mutation with Berardinelli-Seip Congenital Lipodystrophy J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1129 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Szymanski, D. Binns, R. Bartz, N. V. Grishin, W.-P. Li, A. K. Agarwal, A. Garg, R. G. W. Anderson, and J. M. Goodman The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology PNAS, December 26, 2007; 104(52): 20890 - 20895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Jin, L. Cao, Z. Zhao, S. Shen, W. Kiess, D. Zhi, R. Ye, R. Cheng, L. Chen, Y. Yang, et al. Novel BSCL2 gene mutation E189X in Chinese congenital generalized lipodystrophy child with early onset diabetes mellitus Eur. J. Endocrinol., December 1, 2007; 157(6): 783 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Hegele, T. R. Joy, S. A. Al-Attar, and B. K. Rutt Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism J. Lipid Res., July 1, 2007; 48(7): 1433 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yao-Borengasser, N. Rasouli, V. Varma, L. M. Miles, B. Phanavanh, T. N. Starks, J. Phan, H. J. Spencer III, R. E. McGehee Jr., K. Reue, et al. Lipin Expression Is Attenuated in Adipose Tissue of Insulin-Resistant Human Subjects and Increases With Peroxisome Proliferator-Activated Receptor {gamma} Activation. Diabetes, October 1, 2006; 55(10): 2811 - 2818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J R Porter and T G Barrett Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and {beta} cell failure J. Med. Genet., December 1, 2005; 42(12): 893 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Garg Acquired and Inherited Lipodystrophies N. Engl. J. Med., March 18, 2004; 350(12): 1220 - 1234. [Full Text] [PDF]
|
|
|
|
|
|
V. Simha and A. Garg Phenotypic Heterogeneity in Body Fat Distribution in Patients with Congenital Generalized Lipodystrophy Caused by Mutations in the AGPAT2 or Seipin Genes J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5433 - 5437. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
