Abstract
Background: Congenital generalized lipodystrophy (CGL) results from mutations in AGPAT2, encoding 1-acyl-glycerol-3-phosphate-acyltransferase 2 (CGL1; MIM 608594), BSCL2, encoding seipin (CGL2; MIM 269700), CAV1, encoding caveolin1 (CGL3; MIM 612526) or PTRF, encoding polymerase I and transcript release factor (CGL4; MIM 613327). This study aims to investigate the genotype/phenotype relationship and search for a possible pathogenic mechanism in a patient with CGL.
Design: Case report.
Patients and Setting: A 7-day-old child of consanguineous Turkish parents presented with a generalized loss of subcutaneous fat. He had a strikingly enlarged liver, high serum triglycerides, and hyperglycaemia, suggestive for CGL.
Results: A novel homozygous mutation in the acceptor splice site of exon 5 of the BSCL2 gene was found in the genome of the proband. This mutation causes a complex RNA splicing defect and results in two different aberrant seipin proteins, which were normally expressed and localized to the endoplasmic reticulum like wild type protein. Analysis of the patient’s urine showed intermittent elevations of citric acid intermediates and persistently high concentrations of ethylmalonic acid, suggestive of a disturbance of the mitochondrial respiratory chain.
Conclusion: Here we report abnormal urinary organic acid levels, indicative of mitochondrial dysfunction, in a patient with CGL resulting from a novel mutation in BSCL2. Our findings suggest for the first time an association between CGL and secondary mitochondrial dysfunction.
Competing interests: None declared.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Agarwal AK et al (2002) AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31:21–23
Agarwal AK et al (2003) Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 88:4840–4847
Agarwal AK et al (2004) Genetic basis of congenital generalized lipodystrophy. Int J Obes Relat Metab Disord 28:336–339
Ausubel FM, Brent R, Kingston R, Moore D, Seidman JJ, Smith J, Struhl K (1993) Current protocols in molecular biology. Wiley, New York
Bhayana S et al (2002) Cardiomyopathy in congenital complete lipodystrophy. Clin Genet 61:283–287
Blau N, Duran M, Blaskovics ME, Gibson KM (2003) In: Blau N, Duran M, Blaskovics ME, Gibson KM (eds) Physician's guide to the laboratory diagnosis of metabolic diseases. Springer, Berlin
Boutet E et al (2009) Seipin deficiency alters fatty acid Delta9 desaturation and lipid droplet formation in Berardinelli-Seip congenital lipodystrophy. Biochimie 91:796–803
Fei W et al (2008) Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol 180:473–482
Friguls B et al (2009) Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy in an infant with homozygous E189X BSCL2 mutation. Eur J Med Genet 52:14–16
Garg A (2004) Acquired and inherited lipodystrophies. N Engl J Med 350:1220–1234
Hayashi YK et al (2009) Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest 119:2623–2633
Hegele RA et al (2007) Thematic review series: Adipocyte Biology Lipodystrophies: windows on adipose biology and metabolism. J Lipid Res 48:1433–1444
Huang-Doran I et al (2010) Lipodystrophy: metabolic insights from a rare disorder. J Endocrinol 207:245–255
Ito D et al (2008) Characterization of seipin/BSCL2, a protein associated with spastic paraplegia 17. Neurobiol Dis 31:266–277
Jeninga EH, Kalkhoven E (2010) Central players in inherited lipodystrophies. Trends Endocrinol Metab 21:581–588
Kelley DE et al (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51:2944–2950
Kim CA et al (2008) Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab 93:1129–1134
Klar A et al (1993) Cardiomyopathy in lipodystrophy and the specificity spillover hypothesis. Isr J Med Sci 29:50–52
Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307:384–387
Lundin C et al (2006) Membrane topology of the human seipin protein. FEBS Lett 580:2281–2284
Lupsa BC et al (2010) Cardiomyopathy in congenital and acquired generalized lipodystrophy: a clinical assessment. Medicine (Baltimore) 89:245–250
Magre J et al (2001) Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365–370
Ortegren U et al (2007) A new role for caveolae as metabolic platforms. Trends Endocrinol Metab 18:344–349
Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185–194
Payne VA et al (2008) The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation. Diabetes 57:2055–2060
Rinaldo P (2008) In: Blau N, Duran M, Gibson KM (eds) Laboratory guide to the methods in biochemical genetics. Springer, Berlin, p 137
Savage DB et al (2007) Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 87:507–520
Sleigh A et al (2011) Mitochondrial dysfunction in patients with primary congenital insulin resistance. J Clin Invest 121:2457–2461
Szymanski KM et al (2007) The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci USA 104:20890–20895
van de Graaf SF et al (2006) Direct interaction with Rab11a targets the epithelial Ca2+ channels TRPV5 and TRPV6 to the plasma membrane. Mol Cell Biol 26:303–312
Van Maldergem L et al (2002) Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet 39:722–733
Windpassinger C et al (2004) Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 36:271–276
Acknowledgments
We thank Dr. K. Wagner (Medical University, Graz, Austria) for the seipin plasmid construct, Dr. B. Prinsen, and M. de Sain-van der Velden (Department of Metabolic Diseases, UMC Utrecht, Utrecht, The Netherlands) for their help with the organic acid analysis, and Dr. S.F. van de Graaf and Drs. H.S. Schipper (Department of Metabolic Diseases, UMC Utrecht, Utrecht, The Netherlands) for assistance with confocal immunofluorescence microscopy and helpful discussions, respectively.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Wolfgang Sperl.
Electronic Supplementary material
Appendices
Synopsis
Secondary mitochondrial dysfunction in Congenital Generalized Lipodystrophy type 2 (CGL2).
Author Contributions
EHJ and NH conducted experiments, MV and JMPJB performed clinical assessments of the patient, NMVD supervised organic acid analyses, MV, RB, and EK supervised the study, and EHJ, MV, and EK wrote the manuscript.
Guarantor
Dr. E. Kalkhoven, Department of Metabolic and Endocrine Diseases, UMC Utrecht, Room KE.03.139.2, Lundlaan 6, 3584 EA Utrecht, The Netherlands. Phone: +31 88–7554258; Fax: +31-88-7554295. E-mail: e.kalkhoven@umcutrecht.nl.
Competing Interest Statement
The authors have nothing to declare.
Details of Funding
This study was supported by the research programme of The Netherlands Metabolomics Centre, which is part of The Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). The authors confirm independence from the funding body; the content of the article has not been influenced by the funding body.
Details of Ethical Approval
No ethical approval was required for this research study.
Patient Consent Statement
Informed consent for this study was obtained from the parents of the patient.
Rights and permissions
Copyright information
© 2011 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Jeninga, E.H. et al. (2011). A Patient with Congenital Generalized Lipodystrophy Due To a Novel Mutation in BSCL2: Indications for Secondary Mitochondrial Dysfunction. In: JIMD Reports - Case and Research Reports, 2012/1. JIMD Reports, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_86
Download citation
DOI: https://doi.org/10.1007/8904_2011_86
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-25751-3
Online ISBN: 978-3-642-25752-0
eBook Packages: MedicineMedicine (R0)