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.
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.
Authors: J Magré; M Delépine; E Khallouf; T Gedde-Dahl; L Van Maldergem; E Sobel; J Papp; M Meier; A Mégarbané; A Bachy; A Verloes; F H d'Abronzo; E Seemanova; R Assan; N Baudic; C Bourut; P Czernichow; F Huet; F Grigorescu; M de Kerdanet; D Lacombe; P Labrune; M Lanza; H Loret; F Matsuda; J Navarro; A Nivelon-Chevalier; M Polak; J J Robert; P Tric; N Tubiana-Rufi; C Vigouroux; J Weissenbach; S Savasta; J A Maassen; O Trygstad; P Bogalho; P Freitas; J L Medina; F Bonnicci; B I Joffe; G Loyson; V R Panz; F J Raal; S O'Rahilly; T Stephenson; C R Kahn; M Lathrop; J Capeau Journal: Nat Genet Date: 2001-08 Impact factor: 38.330
Authors: L Van Maldergem; J Magré; T E Khallouf; T Gedde-Dahl; M Delépine; O Trygstad; E Seemanova; T Stephenson; C S Albott; F Bonnici; V R Panz; J L Medina; P Bogalho; F Huet; S Savasta; A Verloes; J J Robert; H Loret; M De Kerdanet; N Tubiana-Rufi; A Mégarbané; J Maassen; M Polak; D Lacombe; C R Kahn; E L Silveira; F H D'Abronzo; F Grigorescu; M Lathrop; J Capeau; S O'Rahilly Journal: J Med Genet Date: 2002-10 Impact factor: 6.318
Authors: Christian Windpassinger; Michaela Auer-Grumbach; Joy Irobi; Heema Patel; Erwin Petek; Gerd Hörl; Roland Malli; Johanna A Reed; Ines Dierick; Nathalie Verpoorten; Thomas T Warner; Christos Proukakis; Peter Van den Bergh; Christine Verellen; Lionel Van Maldergem; Luciano Merlini; Peter De Jonghe; Vincent Timmerman; Andrew H Crosby; Klaus Wagner Journal: Nat Genet Date: 2004-02-22 Impact factor: 38.330
Authors: Alison Sleigh; Philippa Raymond-Barker; Kerrie Thackray; David Porter; Mensud Hatunic; Alessandra Vottero; Christine Burren; Catherine Mitchell; Martin McIntyre; Soren Brage; T Adrian Carpenter; Peter R Murgatroyd; Kevin M Brindle; Graham J Kemp; Stephen O'Rahilly; Robert K Semple; David B Savage Journal: J Clin Invest Date: 2011-05-09 Impact factor: 14.808