Diabetes, Metabolic Syndrome and Obesity (Oct 2020)
Cbl Proto-Oncogene B (CBLB) c.197A>T Mutation Induces Mild Metabolic Dysfunction in Partial Type I Multiple Symmetric Lipomatosis (MSL)
Abstract
Ke Chen,1 Xinxing Wan,1 Liling Zhao,1 Shaoli Zhao,1 Lin Peng,2 Wenjun Yang,1 Jingjing Yuan,1 Liyong Zhu,3 Zhaohui Mo1 1Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Department of Nephrology, The First Hospital of Changsha, Changsha, Hunan 410005, People’s Republic of China; 3Department of General Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of ChinaCorrespondence: Zhaohui Mo Tel/Fax +86 731 88618006Email [email protected]: Multiple symmetric lipomatosis (MSL) is a rare disease showing chronic progression of multiple, symmetrical, and non-encapsulated subcutaneous lipoma. The cause of the disease remains unknown.Patients and Methods: This study reported and summarized 13 sporadic cases of Type I MSL patients in terms of histopathology and cellular and molecular biology and assessed the CBLB c.197A>T mutation in the IRS1-PI3K-Akt pathway.Results: The clinical data showed that these 13 Type I patients were all male with a mean age of 57.0 ± 6.6 years old and consumed alcohol heavily. The laboratory tests revealed that most of the patients had hyperuricemia, diabetes, hyperinsulinemia, or insulin resistance; however, their blood lipid levels were close to a normal range. The imaging data exhibited lipomas that only occurred subcutaneously but not viscerally, ie, Types Ia (15.4%), Ib (30.8%), and Ic (53.8%). The molecular analyses of adipocytes of isoprenaline stimulated human adipose tissue-derived mesenchymal stromal cells (hADSCs) isolated from the adipose tissue lipoma-like masses (ATLLM) demonstrated that these adipocytes did not express UCP-1. The Cbl proto-oncogene B (CBLB), an E3 ubiquitin-protein ligase, was associated with insulin resistance and obesity and was mutated (ie, CBLB c.197A>T) in four MSL patients after the whole genome and Sanger sequencing of the blood samples. Furthermore, the CBLB c.197A>T mutation induced hADSC resistance to insulin by inactivation of the IRS-1-PI3K-AKT pathway.Conclusion: This study analyzed clinical, histopathological, and cellular and molecular biological characterizations of 13 Type I MSL patients and identified the CBLB c.197A>T heterozygous mutation that could be responsible for MSL metabolic dysfunction or even MSL development.Keywords: multiple symmetric lipomatosis, MSL, manifestation, characterization, CBLB
