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Epigenomics AG Berlin, Kleine Präsidentenstr. 1, 10178 Berlin, Germany
¹ Institute of Human Genetics, Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
² Institute for Human Genetics, Ernst-Moritz-Arndt University, Fleischmannstrasse 42/44, 17489 Greifswald, Germany
³ University Children’s Hospital, Department of Perinatology: Gerhard-Hauptmann-Str. 35, 39108 Magdeburg, Germany

(Requests for offprints should be addressed to T Brune who is now at Universitätsklinikum Magdeburg, Zentrum für Kinderheilkunde, Gerhard-Hauptmann-Str. 35, D-39108 Magdeburg, Germany; Email: thomas.brune{at}med.ovgu.de)

(R Cortese and F Eckhardt contributed equally to this work)

Mutations in the LMNA gene cause various phenotypes including partial lipodystrophy, muscular dystrophies, and progeroid syndromes. The specific mutation position within the LMNA sequence can partially predict the phenotype, but the underlying mechanisms for the development of these different phenotypes are still unclear. To investigate whether different DNA methylation patterns contribute to the development of different phenotypes caused by LMNA mutations, we analyzed a panel of ten candidate genes related to fat metabolism, aging, and a tendency to different methylation patterns: CSPG2, ESR1, IGF1R, IGFR2, LMNA, MLH1, RANBP1, RARB, ZMPSTE24, and TGFBR1. We studied two independent families each comprising three individuals affected by familial partial lipodistrophy type 2 (FPLD2). Affected members in each family carried two different mutations of the LMNA gene (R482L and R471G respectively). In addition, we analyzed four progeria patients (2xLMNA/C G608G, 1xLMNA/C S143F, and 1xZMPSTE24 IVS9-Ex10) and seven healthy adults. The gene encoding retinoic acid receptor B (RARB) showed a higher methylation in all six patients with FPLD2 when compared with the progeria patients with other LMNA mutations as well as the healthy controls (P<0.05). All other investigated genes showed no difference in the methylation patterns between the groups. A drug-induced inhibition of the retinol pathway is discussed as the key pathway for developing HAART-associated lipodystrophy and our data support a possible role of the retinol pathway in the development of lipodystrophy phenotypes.