Molecular genetic, histologic, immunhistochemical and functional characterization of adipose tissue from patients with Multiple Symmetric Lipomatosis

多发性对称性脂肪瘤病是一种罕见的脂肪组织疾病，估计发病率为1：25,000。MSL可以被描述为皮下脂肪组织的区域性良性肿瘤性生长。当病情发展到晚期时，这种疾病几乎总是会变得具有破坏性。可能的合并症还没有得到很好的探索。到目前为止，唯一有效的治疗方法是手术切除或吸脂。常染色体显性遗传方式的家族性病例已被记录在案。在过去的一年半里，我们收集了25名患者的独特队列，其中包括4例家族性病例。在2个有多个患病个体的家系中使用外显子组测序，我们能够识别出2个潜在的致病变异。作为候选基因之一，SHC1因其在脂肪细胞调节中的作用，尤其是参与可能的线粒体介导的衰老过程(SHC1的p66亚型)而被广泛研究。我们已经从MSL患者的患区和非患区分离并培养了间充质干细胞(=人类脂肪组织来源的干细胞)。我们最初的目标是探索使用原代hASCs研究MSL的基本方法，我们已经能够将外显子组测序的线索转化为使用Western blotting的蛋白质分析。这些实验的结果为理解MSL的发病机制提供了有趣的起点。将临床评估和组织学检查与一系列复杂的分子遗传学和分子生物学方法相结合，是我们建议的一项资产。我们期望首次对MSL的宏观、微观和分子表型有全面的了解。结果将是深远的，因为它们不仅为MSL患者提供了更好的诊断选择的第一步，而且它们可能会带来关于基本脂肪细胞生物学的新知识。

Multiple Symmetric Lipomatosis (= MSL= Launois-Bensaude disease MIM# 151800) is a rare disorder of the adipose tissue with an estimated incidence of 1:25,000. MSL can be described as regional benign neoplastic growth of the subcutaneous fat tissue. When advanced, the disease almost always becomes mutilating. Possible comorbidities are not well explored. The only effective therapy to date is surgical removal or liposuction. Familial cases displaying autosomal dominant mode of inheritance have been documented. In the past 1 ½ years we have gathered a unique cohort of 25 patients including 4 familial cases. Using exome sequencing in 2 families with multiple affected individuals we were able to identify 2 potentially causative variants. One of the candidates, SHC1 has been extensively studied for its implication in fat cell regulation and especially for its involvement in likely mitochondrially mediated ageing processes (p66 isoform of SHC1). We have isolated and cultivated mesenchymal stem cells from affected and unaffected regions in MSL patients (=human adipose tissue derived stem cells, hASCs). Surpassing our initial goal of exploring the principle method of using primary hASCs to study MSL we have already been able to translate clues from exome sequencing into protein analysis using Western blotting. Results from these experiments present interesting starting points in the understanding of MSL pathogenesis. The combination of clinical assessment as well as histological examination with an array of sophisticated molecular genetic and molecular biology methods is an asset of our proposal. We expect, for the first time, to gain comprehensive insight into the macroscopic, microscopic and molecular phenotype of MSL. Results will be far reaching in the sense that not only they provide the first step towards better diagnostic options for MSL patients but they will likely bring forth new knowledge about basic fat cell biology.