遗传 ›› 2022, Vol. 44 ›› Issue (10): 926-936.doi: 10.16288/j.yczz.22-222
叶静雅1(), 黄爱洁1, 付真真1, 龚颖芸1, 杨洪远2, 周红文1()
收稿日期:
2022-06-30
修回日期:
2022-09-12
出版日期:
2022-10-20
发布日期:
2022-09-26
通讯作者:
周红文
E-mail:yezi88999@163.com;drhongwenzhou@njmu.edu.cn
作者简介:
叶静雅,博士,医师,研究方向:内分泌与代谢病。E-mail: 基金资助:
Jingya Ye1(), Aijie Huang1, Zhenzhen Fu1, Yingyun Gong1, Hongyuan Yang2, Hongwen Zhou1()
Received:
2022-06-30
Revised:
2022-09-12
Online:
2022-10-20
Published:
2022-09-26
Contact:
Zhou Hongwen
E-mail:yezi88999@163.com;drhongwenzhou@njmu.edu.cn
Supported by:
摘要:
先天性全身性脂肪萎缩(congenital generalized lipodystrophy,CGL)是一种极端罕见的常染色体隐性遗传病,表现为明显的全身脂肪极度缺失,肌肉感明显,并伴有一系列的代谢指标异常,包括严重的胰岛素抵抗,高血糖,高脂血症,脂肪肝以及黑棘皮等。本文针对1例CGL患者及其家系进行研究。先证者为19岁年轻女性,自幼皮下脂肪缺如,血清瘦素水平仅0.14 μg/L。对患者及其亲属(父母、弟弟)进行全基因组检测,显示该患者BSCL2基因5号外显子存在复合杂合突变(c.560A>G和c.565G>T),c.560A>G突变导致对应编码的187位的氨基酸由酪氨酸突变为半胱氨酸(p.Y187C),从而引起BSCL2编码的SEIPIN蛋白发生错义突变;c.565 G>T突变引起对应编码的189位氨基酸转为终止密码子(p.E189X),产生蛋白截短突变。经Sanger测序验证,患者父亲携带c.565G>T杂合突变,患者母亲携带c.560A>G杂合突变,患者弟弟未携带BSCL2基因致病性突变。本研究通过转染突变p.Y187C质粒至HEK293细胞,观察到SEIPIN蛋白量及与甘油-3-磷酸酰基转移酶(glycerol-3-phosphate acyltransferase, GPAT3)互作减少;原代培养的患者皮肤成纤维细胞体外功能实验表明,患者的SEIPIN蛋白量明显低于正常健康人,加入组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACis)可部分挽救SEIPIN蛋白表达。此外,油酸刺激下患者皮肤成纤维细胞脂滴小于正常健康人。本文同时综述国内外既往文献中报道的BSCL2基因突变位点,丰富了CGL的临床表型谱和致病基因突变谱,有助于提高临床医生对CGL的临床诊治和致病机制的理解。
叶静雅, 黄爱洁, 付真真, 龚颖芸, 杨洪远, 周红文. BSCL2基因复合杂合突变导致先天性全身性脂肪萎缩的分子机制研究[J]. 遗传, 2022, 44(10): 926-936.
Jingya Ye, Aijie Huang, Zhenzhen Fu, Yingyun Gong, Hongyuan Yang, Hongwen Zhou. A study of congenital generalized lipodystrophy (CGL) caused by BSCL2 gene mutation[J]. Hereditas(Beijing), 2022, 44(10): 926-936.
表1
CGL家系实验室检查指标"
检查项目 | 正常值范围 | 患者 | 父亲 | 母亲 | 弟弟 |
---|---|---|---|---|---|
糖化血红蛋白(%) | 4.0~6.0 | 10.6 | 5.5 | 4.8 | 5.0 |
谷丙转氨酶(U/L) | 7.0~40.0 | 42.1 | 35 | 15 | 12 |
谷草转氨酶(U/L) | 13.0~35.0 | 20.5 | 26 | 19 | 18 |
碱性磷酸酶(U/L) | 30.0~120.0 | 114.9 | 54 | 78 | 118 |
甘油三酯(mmol/L) | 0~2.25 | 2.31 | 0.6 | 0.82 | 1.19 |
胆固醇(mmol/L) | 3.0~5.7 | 2.98 | 3.92 | 3.87 | 3.02 |
高密度胆固醇酯(mmol/L) | 1.03~1.55 | 0.82 | 2.1 | 1.88 | 1.32 |
低密度胆固醇酯(mmol/L) | 2.6~4.1 | 1.78 | 1.6 | 1.77 | 1.33 |
促甲状腺素(mIU/L) | 0.27~4.2 | 0.834 | 0.662 | 1.840 | 1.890 |
游离三碘甲状腺原氨酸(pmol/L) | 3.1~6.8 | 4.3 | 5.23 | 5.28 | 6.89 |
游离甲状腺素(pmol/L) | 12.0~22.0 | 13.89 | 20.70 | 18.46 | 22.79 |
空腹血糖(mmol/L) | 3.9~6.1 | 16.37 | 6.21 | 5.11 | 5.33 |
2 h血糖(mmol/L) | < 7.8 | 18.85 | 5.04 | 6.7 | 6.61 |
空腹胰岛素(pmol/L) | 17.8~173.0 | 1001 | 47 | 53 | 30 |
2 h胰岛素(pmol/L) | 1460 | 539 | 483 | 393 | |
空腹C肽(pmol/L) | 370.0~1470.0 | 1512 | 82 | 209 | 170 |
2 h C肽(pmol/L) | 2521 | 1505 | 2248 | 1798 | |
瘦素(μg/L) | 0.14 | 0.55 | 3.80 | 1.53 |
图2
SEIPIN突变的功能特性 A和B:携带HA标签p.Y187C 质粒及野生型质粒转染HEK293细胞后进行蛋白质印迹(A)和免疫荧光观察(B)结果。蓝色:DAPI,红色:HA-SEIPIN。标尺:5 μm。C:免疫沉淀HA标记的SEIPIN的蛋白质印迹及其与标记的GPAT3的相互作用。p.T78A:无义突变;p.Y187C:腺嘌呤到鸟嘌呤替换突变。D:OA刺激后,来自年龄性别匹配的健康志愿者(Ctrl)和CGL患者的皮肤成纤维细胞脂滴染色。蓝色:DAPI;绿色:Bodipy。标尺:5 μm。E:蛋白质印迹观察HDACis (SAHA或Panobinostat)处理48 h的人成纤维细胞中SEIPIN含量。F和G:脂滴染色(D)和蛋白印迹(E)统计分析图,*P<0.05。"
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