Garg Abhimanyu, Xing Chao, Agarwal Anil K, Westfall Aundrea K, Tomchick Diana R, Zhang Xunzhi, Xing Michelle, Brown Rebecca J
Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX.
McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX.
Diabetes. 2025 Mar 1;74(3):427-438. doi: 10.2337/db24-0624.
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 patients with unexplained FPL identified two unrelated patients with FPL 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 sequencing and proteomics analysis of skin fibroblasts revealed significantly higher RNA and protein expression of NOTCH3 and activation of widespread senescence pathways in the patients with FPL versus control study participants. 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 patients without obesity but with early- or childhood-onset diabetes.
Molecular genetic defects in some ultra-rare subtypes of familial partial lipodystrophies (FPLs) remain unidentified. We investigated whether novel gene variants explain FPL in some undiagnosed patients. We found novel heterozygous gain-of-function missense variants clustered in the heterodimerization domain of the negative regulatory region of NOTCH3 in three unrelated families with FPL. Our study suggests that gain-of-function missense variants in the heterodimerization domain of NOTCH3 cause a novel subtype of FPL by activation of senescence pathways.
尽管已阐明了几种脂肪营养不良综合征的分子遗传基础，但某些极其罕见的家族性脂肪营养不良亚型中的分子缺陷仍未明确。我们分析了一个未确诊的常染色体显性遗传性家族性部分脂肪营养不良（FPL）家系中4名患病女性和2名未患病女性的全外显子测序（WES）数据，仅在NOTCH3中鉴定出一个符合筛选标准的新型杂合变体p.Ala1603Tyr。对222例不明原因FPL患者的WES数据进行进一步分析，发现另外两名无关的FPL患者携带新型杂合NOTCH3变体（p.Cys1600Tyr和p.Gln1552Pro）。所有变体均聚集在NOTCH3负调控区域的异二聚化结构域中。对皮肤成纤维细胞进行的RNA测序和蛋白质组学分析显示，与对照研究参与者相比，FPL患者中NOTCH3的RNA和蛋白质表达显著更高，且广泛的衰老途径被激活。NOTCH3在脂肪组织中高度表达，在发育模式形成、细胞命运决定、细胞存活调节和增殖中发挥许多关键作用。我们得出结论，NOTCH3负调控区域的功能获得性错义变体通过激活衰老途径导致一种新型的FPL亚型。对于没有肥胖但患有早发性或儿童期糖尿病的患者，应考虑这种新型的FPL。
某些极其罕见的家族性部分脂肪营养不良（FPL）亚型中的分子遗传缺陷仍未明确。我们调查了新型基因变体是否能解释一些未确诊患者的FPL病因。我们在三个无关的FPL家族中发现新型杂合功能获得性错义变体聚集在NOTCH3负调控区域异二聚化结构域中。我们的研究表明，NOTCH3异二聚化结构域中的功能获得性错义变体通过激活衰老途径导致一种新型的FPL亚型。
