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.

中文翻译：

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功能获得 NOTCH3 变体由于衰老途径的激活而导致家族性部分脂肪代谢障碍


尽管阐明了几种脂肪代谢障碍综合征的分子遗传基础，但一些极其罕见的家族性脂肪营养不良亚型的分子缺陷仍未确定。我们分析了来自未诊断的常染色体显性遗传性家族性部分脂肪代谢障碍 （FPL） 家系的 4 名受影响女性和 2 名未受影响的女性的全外显子组测序 （WES） 数据，并仅确定了一种新的杂合变异，即 NOTCH3 中的 p.Ala1603Tyr 符合过滤标准。对 222 名不明原因的 FPL 患者的 WES 数据的进一步分析确定了两名具有新型杂合子 p.Cys1600Tyr 和 p.Gln1552Pro， NOTCH3 变异的无关 FPL 患者。所有变体都聚集在 NOTCH3 负调节区的异二聚化结构域中。皮肤成纤维细胞的 RNA-Seq 和蛋白质组学分析显示，与对照组相比，FPL 患者 NOTCH3 的 RNA 和蛋白表达以及广泛衰老途径的激活显著升高。NOTCH3 在脂肪组织中高度表达，并在发育模式、细胞命运决定、细胞存活和增殖调节中发挥许多关键作用。我们得出结论，NOTCH3 负调节区的功能获得性错义变异通过激活衰老途径导致 FPL 的新亚型。对于患有早期或儿童期发病糖尿病的非肥胖患者，应考虑这种新型 FPL。