Dermatology Hospital, Southern Medical University, Guangzhou, China.
Department of Ophthalmology, Peking University First Hospital, Beijing, China.
Br J Dermatol. 2024 Oct 17;191(5):805-815. doi: 10.1093/bjd/ljae291.
Lipid metabolism has essential roles in skin barrier formation and the regulation of skin inflammation. Lipid homeostasis regulates skin melanogenesis, although the underlying mechanism remains largely unknown. Sterol regulatory element binding protein 1 (SREBP-1) is a key transcription factor essential for cellular lipid metabolism. Loss-of-function variants in SREBF1 are responsible for autosomal-dominant ichthyosis follicularis, alopecia and photophobia syndrome, emphasizing the significance of lipid homeostasis in skin keratinization.
To identify the genetic basis of a new entity featuring diffuse skin hyperpigmentation with congenital cataracts, and to unravel the underlying mechanism for the pathogenesis of the SREBF1 variant.
Whole-exome sequencing was performed to identify underlying genetic variants. Quantitative polymerase chain reaction, Western blot and immunofluorescence staining were used to assess the expression and the subcellular localization of the SREBF1 variant. The transcriptional activity of mutant SREBP-1 was determined by a luciferase reporter assay. A transgenic zebrafish model was constructed.
Two unrelated patients presented with generalized skin hyperpigmentation with skin xerosis, congenital cataracts and extracutaneous symptoms. We identified a de novo nonsense variant c.1289C>A (p.Ser430*) in SREBF1 in both patients. The variant encoded a truncated protein that showed preferential nucleus localization, in contrast to wild-type SREBP-1 which - in sterol-sufficient conditions - is mainly localized in the cytoplasm. The luciferase reporter assay revealed that the p.Ser430* mutant exhibited enhanced transcriptional activity. Cultured patient primary melanocytes showed increased melanin synthesis vs. those from healthy controls. At 35 days postfertilization, the p.Ser430* transgenic zebrafish model exhibited more black spots, along with upregulated expression of melanogenic genes.
We demonstrated that a gain-of-function variant of SREBF1 causes a previously undescribed disorder characterized by generalized skin hyperpigmentation and congenital cataracts. Our study reveals the involvement of SREBP-1 in melanogenesis and lens development, and paves the way for the development of novel therapeutic targets for skin dyspigmentation or cataracts.
脂质代谢在皮肤屏障形成和皮肤炎症调节中起着重要作用。脂质稳态调节皮肤黑色素生成，尽管其潜在机制在很大程度上仍不清楚。固醇调节元件结合蛋白 1（SREBP-1）是细胞脂质代谢所必需的关键转录因子。SREBF1 的功能丧失变体负责常染色体显性遗传性滤泡性鱼鳞病、脱发和畏光综合征，强调了脂质稳态在皮肤角化中的重要性。
鉴定一种具有弥漫性皮肤色素沉着和先天性白内障的新实体的遗传基础，并阐明 SREBF1 变体发病机制的潜在机制。
进行全外显子组测序以鉴定潜在的遗传变异。使用定量聚合酶链反应、Western blot 和免疫荧光染色来评估 SREBF1 变体的表达和亚细胞定位。通过荧光素酶报告基因测定来确定突变 SREBP-1 的转录活性。构建了转基因斑马鱼模型。
两名无关的患者表现为全身性皮肤色素沉着伴皮肤干燥、先天性白内障和皮肤外症状。我们在两名患者中均发现了 SREBF1 中的从头无义变异 c.1289C>A（p.Ser430*）。该变体编码的截短蛋白显示优先核定位，而野生型 SREBP-1 在甾醇充足的条件下主要定位于细胞质。荧光素酶报告基因测定显示，p.Ser430* 突变体表现出增强的转录活性。与健康对照相比，培养的患者原代黑素细胞显示出增加的黑色素合成。在受精后 35 天，p.Ser430* 转基因斑马鱼模型表现出更多的黑斑，同时上调了黑色素生成基因的表达。
我们证明了 SREBF1 的功能获得性变体导致一种以前未描述的疾病，其特征为全身性皮肤色素沉着和先天性白内障。我们的研究揭示了 SREBP-1 在黑色素生成和晶状体发育中的作用，并为皮肤色素沉着或白内障的新型治疗靶点的开发铺平了道路。
