Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
School of Biotechnology and Biomolecular Sciences,University of New South Wales, Sydney 999029, Australia.
Yi Chuan. 2022 Oct 20;44(10):926-936. doi: 10.16288/j.yczz.22-222.
Congenital generalized lipodystrophy (CGL) is an extremely rare genetic disease mainly characterized by absence of whole-body adipose tissue and metabolic dysfunctions such as insulin resistance, diabetes mellitus, hypertriglyceridemia, hepatic steatosis, and acanthosis nigricans. In this study, we reported a novel case of a young woman patient with CGL. The patient came to the hospital for early-onset lipodystrophy and diabetes. She was 19-year-old with a height of 160 cm, a weight of 46 kg, BMI of 17.9 kg/m, and a serum leptin level of 0.14 μg/L. Genomic DNA was extracted from blood samples of the patient and her family members, including her mother, father and brother. Genetic analysis revealed compound heterozygous mutations of the BSCL2 gene (c.560A>G and c.565G>T) in the patient. Her father carried a heterozygous mutation (c.565G>T), and her mother carried a heterozygous mutation (c.560A>G) in the BSCL2 gene. The mutant p.Y187C plasmid was transfected into HEK293T cells. The protein expression of SEIPIN and its interaction with glycerol-3-phosphate acyltransferase (GPAT3) were observed to be reduced. In addition, based on primary cultured skin fibroblasts from the patient, SEIPIN protein was decreased, and lipid droplets were much smaller when fatty acid was stimulated compared with those observed from healthy subject controls. However, histone deacetylase inhibitors (HDACis) was found capable of rescuing SEIPIN protein in fibroblasts of the patient. In addition, we further summarized and discussed gene mutations of BSCL2 reported in the current literature. Collectively, these findings have expanded the clinical phenotype and pathogenic gene spectrum of CGL, which might help clinicians to achieve better management of lipodystrophy.
先天性全身性脂肪营养不良（CGL）是一种极为罕见的遗传性疾病，主要表现为全身脂肪组织缺失和代谢功能障碍，如胰岛素抵抗、糖尿病、高甘油三酯血症、脂肪肝和黑棘皮病。本研究报道了一例 CGL 年轻女性患者。患者因早发性脂肪营养不良和糖尿病就诊。她 19 岁，身高 160cm，体重 46kg，BMI 为 17.9kg/m，血清瘦素水平为 0.14μg/L。从患者及其家庭成员（包括母亲、父亲和哥哥）的血液样本中提取基因组 DNA。遗传分析显示患者携带 BSCL2 基因的复合杂合突变（c.560A>G 和 c.565G>T）。其父亲携带杂合突变（c.565G>T），母亲携带杂合突变（c.560A>G）。将突变型 p.Y187C 质粒转染至 HEK293T 细胞，观察到 SEIPIN 蛋白表达及其与甘油-3-磷酸酰基转移酶（GPAT3）的相互作用减少。此外，基于患者的原代培养皮肤成纤维细胞，与健康对照受试者相比，SEIPIN 蛋白减少，脂肪酸刺激时的脂滴小得多。然而，组蛋白去乙酰化酶抑制剂（HDACis）被发现能够挽救患者成纤维细胞中的 SEIPIN 蛋白。此外，我们进一步总结和讨论了目前文献中报道的 BSCL2 基因突变。总之，这些发现扩展了 CGL 的临床表型和致病基因谱，有助于临床医生更好地管理脂肪营养不良。
