Abhimanyu Garg, Chao Xing, Anil K. Agarwal, Aundrea K. Westfall, Diana R. Tomchick, Xunzhi Zhang, Michelle Xing, Rebecca J. Brown
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引用次数: 0
Abstract
Despite elucidation of the molecular genetic basis of several lipodystrophy syndromes, molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We analyzed whole exome sequencing (WES) data of four affected and two unaffected females from an undiagnosed autosomal dominant familial partial lipodystrophy (FPL) pedigree and identified only one novel heterozygous variant, p.Ala1603Tyr in NOTCH3 meeting the filtering criteria. Further analysis of WES data of 222 unexplained FPL patients identified two unrelated FPL patients with novel heterozygous, p.Cys1600Tyr and p.Gln1552Pro, NOTCH3 variants. All variants were clustered in the heterodimerization domain of the negative regulatory region of NOTCH3. RNA-Seq and proteomics analysis of skin fibroblasts revealed significantly higher RNA and protein expression of NOTCH3 and activation of widespread senescence pathways in the FPL patients versus controls. NOTCH3 is highly expressed in adipose tissue and plays many crucial roles in developmental patterning, cell fate decisions, regulation of cell survival and proliferation. We conclude that gain-of-function missense variants in the negative regulatory region of NOTCH3 cause a novel subtype of FPL by activation of senescence pathways. This novel variety of FPL should be considered for non-obese patients with early- or childhood-onset diabetes mellitus.
期刊介绍:
Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes.
However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.