Multiple Symmetric Lipomatosis - New Aspects of a Forgotten Syndrome. J. Schreml1, A. Lindner1, O. Felthaus2,3, S. Klein2, C. Pallouras4, S. Schreml5, I. Harsch6, T. Meitinger7, T. M. Strom7, J. Altmüller8,1, S. Staubach1, F. G. Hanisch10,11, H. Thiele8, P. Nürnberg8,9,10, L. Prantl2,3 1) Institute of Human Genetics, University of Cologne, Cologne, Germany; 2) Center of Plastic Surgery, Department of Trauma Surgery, University Medical Center Regensburg, Regensburg, Germany; 3) Applied Stem Cell Research Center Regensburg, University of Regensburg, Regensburg, Germany; 4) Dermatology, University of Cologne, Cologne, Germany; 5) Department of Dermatology, University Medical Center Regensburg, Regensburg, Germany; 6) Internal Medicine II, Endocrinology/Diabetology, Thüringen-Kliniken Georgius Agricola, Saalfeld/Saale, Germany; 7) Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; 8) Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; 9) Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; 10) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; 11) Medical Faculty, Institute of Biochemistry II, University of Cologne, Cologne, Germany.

   Multiple Symmetric Lipomatosis (MSL, OMIM# 151800) is a rare disorder of the adipose organ with regional, tumorous growth of non-encapsulated adipose tissue reaching often disfiguring proportions. Knowledge on the phenotype, etiology and molecular mechanisms involved is scarce. Patients are suffering from extremely reduced quality of life and the only effective therapy to date is surgery. MSL is relatively unknown to many health care professionals, often mistaken for obesity and therefore likely underdiagnosed. Most cases are considered sporadic and only few familial cases have been reported with both, mitochondrial and autosomal dominant, mode of inheritance suggested. We have collected a total of 24 patients, among them 12 patients from 5 families and 12 sporadic cases. All pedigrees are compatible with autosomal dominant inheritance with one family showing paternal transmission. Previous studies have suggested that MSL tissue differs on a histological and molecular biological level from regular white fat. To further characterize these differences we are using human adipose derived stem cells (hASCs) from affected and unaffected adipose tissue from MSL patients and control patients. We have found that patient hASCs exhibit abnormal response towards differentiation stimuli. In absence of differentiation media the stem cells show increased proliferation and spontaneously exhibit pronounced lipid droplet formation after prolonged cultivation. Conversely, under differentiation conditions, patient hASCs show reduced propensity for the final phase of adipocyte differentiation. MicroRNA 183, a driver of adipocyte differentiation, was differentially expressed in the patient cells. Moreover, we observed a shift in the expression of the three isoforms of SHC1, a protein known to be involved in the regulation of fat accumulation, ageing and oxidative stress response, in affected patient cells. We are currently performing proteomics analysis (iTRAQ = isobaric Tags for Relative and Absolute Quantitation) to further investigate the involved signaling pathway(s) and are at the same time performing genetic analysis by exome sequencing of familial cases. Elucidation of the molecular mechanisms involved promises new insight into general adipose tissue biology and regulation. Finally, establishing histological/biochemical hallmarks that can be used for diagnosis in a clinical setting can lead to a dramatic improvement of patient care in the future.

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