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

doi:10.16288/j.yczz.22-222

遗传 ›› 2022, Vol. 44 ›› Issue (10): 926-936.doi: 10.16288/j.yczz.22-222

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

叶静雅¹(), 黄爱洁¹, 付真真¹, 龚颖芸¹, 杨洪远², 周红文¹()

1. 南京医科大学第一附属医院内分泌科,南京 210029
2. 澳大利亚新南威尔士大学生物技术与生物分子科学学院,悉尼 999029,澳大利亚

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: yezi88999@163.com
基金资助:
国家重点研发计划(2018YFA0506904);国家重点研发计划(2019YFA0802701);国家自然科学基金项目(82170882);国家自然科学基金项目(91854122)

A study of congenital generalized lipodystrophy (CGL) caused by BSCL2 gene mutation

Jingya Ye¹(), Aijie Huang¹, Zhenzhen Fu¹, Yingyun Gong¹, Hongyuan Yang², Hongwen Zhou¹()

1. Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
2. School of Biotechnology and Biomolecular Sciences,University of New South Wales, Sydney 999029, Australia

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:
the National Key Research and Development Program(2018YFA0506904);the National Key Research and Development Program(2019YFA0802701);the National Natural Science Foundation of China(82170882);the National Natural Science Foundation of China(91854122)

摘要/Abstract

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。

关键词: 先天性全身性脂肪萎缩, BSCL2/SEIPIN, 成纤维细胞, HDACi, 糖尿病

Abstract:

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/m², 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.

Key words: CGL, BSCL2/SEIPIN, fibroblast, HDACi, diabetes

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.

图/表 4

图1

表1

图2

图3

参考文献 42

[1]	Agarwal AK, Garg A. Genetic disorders of adipose tissue development, differentiation, and death. Annu Rev Genomics Hum Genet, 2006, 7: 175-199. pmid: 16722806
[2]	Agarwal AK, Garg A. Genetic basis of lipodystrophies and management of metabolic complications. Annu Rev Med, 2006, 57: 297-311. pmid: 16409151
[3]	Fei WH, Du XM, Yang HY. Seipin, adipogenesis and lipid droplets. Trends Endocrinol Metab, 2011, 22(6): 204-210. doi: 10.1016/j.tem.2011.02.004
[4]	Haque WA, Shimomura I, Matsuzawa Y, Garg A. Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab, 2002, 87(5): 2395. doi: 10.1210/jcem.87.5.8624
[5]	Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, Jebb SA, Lip GY, O’Rahilly S. Partial leptin deficiency and human adiposity. Nature, 2001, 414(6859): 34-35. doi: 10.1038/35102112
[6]	Pareja-Galeano H, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C, Garatachea N, Gálvez BG, Lucia A, Emanuele E. Circulating leptin and adiponectin concentrations in healthy exceptional longevity. Mech Ageing Dev, 2017, 162: 129-132. doi: S0047-6374(16)30019-7 pmid: 26944227
[7]	Van Maldergem L, Magré J, Khallouf TE, Gedde-Dahl T, Delépine M, Trygstad O, Seemanova E, Stephenson T, Albott CS, Bonnici F, Panz VR, Medina JL, Bogalho P, Huet F, Savasta S, Verloes A, Robert JJ, Loret H, De Kerdanet M, Tubiana-Rufi N, Mégarbané A, Maassen J, Polak M, Lacombe D, Kahn CR, Silveira EL, D'Abronzo FH, Grigorescu F, Lathrop M, Capeau J, O'Rahilly S. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet, 2002, 39(10): 722-733. pmid: 12362029
[8]	Agarwal AK, Simha V, Oral EA, Moran SA, Gorden P, O'Rahilly S, Zaidi Z, Gurakan F, Arslanian SA, Klar A, Ricker A, White NH, Bindl L, Herbst K, Kennel K, Patel SB, Al-Gazali L, Garg A. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab, 2003, 88(10): 4840-4847. doi: 10.1210/jc.2003-030855
[9]	Agarwal AK, Garg A. Seipin: a mysterious protein. Trends Mol Med, 2004, 10(9): 440-444. pmid: 15350896
[10]	Jiang M, Gao MM, Wu CM, He H, Guo XJ, Zhou ZM, Yang HY, Xiao XH, Liu G, Sha JH. Lack of testicular seipin causes teratozoospermia syndrome in men. Proc Natl Acad Sci USA, 2014, 111(19): 7054-7059. doi: 10.1073/pnas.1324025111
[11]	Magré J, Delépine M, Khallouf E, Gedde-Dahl T, Van Maldergem L, Sobel E, Papp J, Meier M, Mégarbané A, Bachy A, Verloes A, d'Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J, BSCL Working Group. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet, 2001, 28(4): 365-370. pmid: 11479539
[12]	Szymanski KM, Binns D, Bartz R, Grishin NV, Li WP, Agarwal AK, Garg A, Anderson RGW, Goodman JM. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci USA, 2007, 104(52): 20890-20895. doi: 10.1073/pnas.0704154104
[13]	Fei WH, Shui GH, Gaeta B, Du XM, Kuerschner L, Li P, Brown AJ, Wenk MR, Parton RG, Yang HY. Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol, 2008, 180(3): 473-482. doi: 10.1083/jcb.200711136 pmid: 18250201
[14]	Salo VT, Belevich I, Li SQ, Karhinen L, Vihinen H, Vigouroux C, Magré J, Thiele C, Hölttä-Vuori M, Jokitalo E, Ikonen E. Seipin regulates ER-lipid droplet contacts and cargo delivery. EMBO J, 2016, 35(24): 2699-2716. pmid: 27879284
[15]	Wang HJ, Becuwe M, Housden BE, Chitraju C, Porras AJ, Graham MM, Liu XN, Thiam AR, Savage DB, Agarwal AK, Garg A, Olarte MJ, Lin QQ, Fröhlich F, Hannibal- Bach HK, Upadhyayula S, Perrimon N, Kirchhausen T, Ejsing CS, Walther TC, Farese RV. Seipin is required for converting nascent to mature lipid droplets. eLife, 2016, 5: e16582.
[16]	BERARDINELLI W. An undiagnosed endocrinometabolic syndrome:report of 2 cases. J Clin Endocrinol Metab, 1954, 14(2): 193-204.
[17]	Magré J, Delépine M, Van Maldergem L, Robert JJ, Maassen JA, Meier M, Panz VR, Kim CA, Tubiana-Rufi N, Czernichow P, Seemanova E, Buchanan CR, Lacombe D, Vigouroux C, Lascols O, Kahn CR, Capeau J, Lathrop M. Prevalence of mutations in AGPAT2 among human lipodystrophies. Diabetes, 2003, 52(6): 1573-1578. pmid: 12765973
[18]	Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol, 2011, 12(11): 722-734. doi: 10.1038/nrm3198
[19]	Miranda DM, Wajchenberg BL, Calsolari MR, Aguiar MJ, Silva JMCL, Ribeiro MG, Fonseca C, Amaral D, Boson WL, Resende BA, De Marco L. Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome. Clin Endocrinol (Oxf), 2009, 71(4): 512-517. doi: 10.1111/j.1365-2265.2009.03532.x
[20]	Qin YY, Zhang X, Xiang LQ, Shan QW, Li SD, Yan J, Lin FQ. A new compound heterozygous mutation of BSCL2 in a chinese zhuang ethnic family with congenital generalized lipodystrophy. Diabetes Metab Syndr Obes, 2019, 12: 2583-2587. doi: 10.2147/DMSO.S207293
[21]	Yang Y, Ma L, Sun JJ, Gong XH, Cai C, Hong WC. The neonatal onset diabetes mellitus of Chinese neonate with congenital generalized lipodystrophy 2:a case report. BMC Endocr Disord, 2022, 22(1): 83.
[22]	Wang MF, Cun ZK, Peng JC, Chen R, Li JW. Type2 congenital generalized lipodystrophy with a heterozygous missense NOTCH2 mutation. Eur J Clin Nutr, 2022, 76(7): 1041-1043. doi: 10.1038/s41430-022-01072-y
[23]	Lu J, Chiang J, Iyer RR, Thompson E, Kaneski CR, Xu DS, Yang CZ, Chen M, Hodes RJ, Lonser RR, Brady RO, Zhuang ZP. Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl. Proc Natl Acad Sci USA, 2010, 107(50): 21665-21670. doi: 10.1073/pnas.1014376107
[24]	Pagac M, Cooper DE, Qi YF, Lukmantara IE, Mak HY, Wu ZY, Tian Y, Liu ZH, Lei M, Du XM, Ferguson C, Kotevski D, Sadowski P, Chen WQ, Boroda S, Harris TE, Liu G, Parton RG, Huang X, Coleman RA, Yang HY. SEIPIN regulates lipid droplet expansion and adipocyte development by modulating the activity of glycerol-3- phosphate acyltransferase. Cell Rep, 2016, 17(6): 1546-1559. doi: 10.1016/j.celrep.2016.10.037
[25]	Pipalia NH, Cosner CC, Huang A, Chatterjee A, Bourbon P, Farley N, Helquist P, Wiest O, Maxfield FR. Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts. Proc Natl Acad Sci USA, 2011, 108(14): 5620-5625. doi: 10.1073/pnas.1014890108
[26]	Munkacsi AB, Chen FW, Brinkman MA, Higaki K, Gutiérrez GD, Chaudhari J, Layer JV, Tong A, Bard M, Boone C, Ioannou YA, Sturley SL. An “exacerbate- reverse” strategy in yeast identifies histone deacetylase inhibition as a correction for cholesterol and sphingolipid transport defects in human Niemann-Pick type C disease. J Biol Chem, 2011, 286(27): 23842-23851. doi: 10.1074/jbc.M111.227645 pmid: 21489983
[27]	Hutt DM, Herman D, Rodrigues APC, Noel S, Pilewski JM, Matteson J, Hoch B, Kellner W, Kelly JW, Schmidt A, Thomas PJ, Matsumura Y, Skach WR, Gentzsch M, Riordan JR, Sorscher EJ, Okiyoneda T, Yates JR, Lukacs GL, Frizzell RA, Manning G, Gottesfeld JM, Balch WE. Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. Nat Chem Biol, 2010, 6(1): 25-33. doi: 10.1038/nchembio.275 pmid: 19966789
[28]	Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science, 2006, 313(5790): 1137-1140. doi: 10.1126/science.1128294 pmid: 16931765
[29]	Jin J, Cao LF, Zhao ZH, Shen SX, Kiess W, Zhi DJ, Ye R, Cheng RQ, Chen L, Yang Y, Luo FH. Novel BSCL2 gene mutation E189X in Chinese congenital generalized lipodystrophy child with early onset diabetes mellitus. Eur J Endocrinol, 2007, 157(6): 783-787. doi: 10.1530/EJE-07-0393
[30]	Antuna-Puente B, Boutet E, Vigouroux C, Lascols O, Slama L, Caron-Debarle M, Khallouf E, Lévy-Marchal C, Capeau J, Bastard JP, Magré J. Higher adiponectin levels in patients with Berardinelli-Seip congenital lipodystrophy due to seipin as compared with 1-acylglycerol-3-phosphate- o-acyltransferase-2 deficiency. J Clin Endocrinol Metab, 2010, 95(3): 1463-1468. doi: 10.1210/jc.2009-1824 pmid: 20097706
[31]	Nishiyama A, Yagi M, Awano H, Okizuka Y, Maeda T, Yoshida S, Takeshima Y, Matsuo M. Two Japanese infants with congenital generalized lipodystrophy due to BSCL2 mutations. Pediatr Int, 2009, 51(6): 775-779. doi: 10.1111/j.1442-200X.2009.02863.x pmid: 19438831
[32]	Simha V, Garg A. Inherited lipodystrophies and hypertriglyceridemia. Curr Opin Lipidol, 2009, 20(4): 300-308. doi: 10.1097/MOL.0b013e32832d4a33 pmid: 19494770
[33]	Patni N, Garg A. Congenital generalized lipodystrophies— new insights into metabolic dysfunction. Nat Rev Endocrinol, 2015, 11(9): 522-534. doi: 10.1038/nrendo.2015.123
[34]	Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P. The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism, 2005, 54(2): 255-263. doi: 10.1016/j.metabol.2004.08.021
[35]	Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med, 2002, 346(8): 570-578. doi: 10.1056/NEJMoa012437
[36]	Mulligan K, Khatami H, Schwarz JM, Sakkas GK, DePaoli AM, Tai VW, Wen MJ, Lee GA, Grunfeld C, Schambelan M. The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab, 2009, 94(4): 1137-1144. doi: 10.1210/jc.2008-1588 pmid: 19174500
[37]	Simha V, Subramanyam L, Szczepaniak L, Quittner C, Adams-Huet B, Snell P, Garg A. Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab, 2012, 97(3): 785-792. doi: 10.1210/jc.2011-2229 pmid: 22170723
[38]	Scroggins BT, Robzyk K, Wang DX, Marcu MG, Tsutsumi S, Beebe K, Cotter RJ, Felts S, Toft D, Karnitz L, Rosen N, Neckers L. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol Cell, 2007, 25(1): 151-159. pmid: 17218278
[39]	Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol, 2007, 25(1): 84-90. pmid: 17211407
[40]	Lu J, Yang CZ, Chen M, Ye DY, Lonser RR, Brady RO, Zhuang ZP. Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease. Proc Natl Acad Sci USA, 2011, 108(52): 21200-21205. doi: 10.1073/pnas.1119181109
[41]	Pipalia NH, Subramanian K, Mao S, Ralph H, Hutt DM, Scott SM, Balch WE, Maxfield FR. Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells. J Lipid Res, 2017, 58(4): 695-708. doi: 10.1194/jlr.M072140 pmid: 28193631
[42]	Ramalingam SS, Parise RA, Ramanathan RK, Lagattuta TF, Musguire LA, Stoller RG, Potter DM, Argiris AE, Zwiebel JA, Egorin MJ, Belani CP. Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res, 2007, 13(12): 3605-3610. pmid: 17510206

编辑推荐

Metrics

www.chinagene.cn
备案号：京ICP备09063187号-4
总访问:,今日访问:,当前在线:

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

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

A study of congenital generalized lipodystrophy (CGL) caused by BSCL2 gene mutation

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 4

参考文献 42

相关文章 15

编辑推荐

Metrics

[1]	杨慧杰, 李德, 白卉泠, 张铭, 黄俊, 袁小青. 一例ALMS1基因复合杂合突变所致的Alstrom综合征的诊疗和基因检测分析[J]. 遗传, 2022, 44(12): 1148-1157.
[2]	沈敏, 顾愹, 应长江, 张梅, 杨涛, 陈阳. 一例胰腺纤维钙化性糖尿病的诊疗和基因检测分析[J]. 遗传, 2022, 44(11): 1079-1086.
[3]	吕承安, 王若然, 孟卓贤. 2型糖尿病进程中胰岛β细胞功能变化的分子机制[J]. 遗传, 2022, 44(10): 840-852.
[4]	张丽雯, 阮梅花, 刘加兰, 贺彩红, 于建荣. 糖尿病领域研发态势分析[J]. 遗传, 2022, 44(10): 824-839.
[5]	曾之扬, 陆佳微, 曹希雅, 王芯悦, 李大力. 一种GLP-1过表达肠类器官构建的方法[J]. 遗传, 2021, 43(7): 694-703.
[6]	曹岚, 李志强, 师咏勇, 刘赟. 端粒长度与2型糖尿病：孟德尔随机化研究与多基因风险评分分析[J]. 遗传, 2020, 42(9): 882-888.
[7]	王玉琢, 张一鸣, 董晓莲, 王学才, 朱建福, 王娜, 江峰, 陈跃, 姜庆五, 付朝伟. 2型糖尿病易感基因SNP位点对生活方式干预降低血糖应答效果的修饰效应[J]. 遗传, 2020, 42(5): 483-492.
[8]	黄鑫,陈永强,徐国良,彭淑红. 脂肪组织DNA甲基化与糖尿病和肥胖的发生发展[J]. 遗传, 2019, 41(2): 98-110.
[9]	胡广东,郝科兴,黄涛,曾维斌,谷新利,王静. 绵羊高效转基因通用型piggyBac转座子载体构建及功能验证[J]. 遗传, 2018, 40(8): 647-656.
[10]	钟翠丽, 李国玲, 莫健新, 全绒, 王豪强, 李紫聪, 吴珍芳, 张献伟. 不同电转仪的电转参数、质粒用量和拓扑结构对猪胎儿成纤维细胞转染效率的影响[J]. 遗传, 2017, 39(10): 930-938.
[11]	王伟, 王玉霜, 黄兰兰, 简子健, 王新华, 刘守仁, 皮文辉. siRNA干扰绵羊胚胎成纤维细胞Lig4基因增加同源重组载体重连修复效率[J]. 遗传, 2016, 38(9): 831-839.
[12]	弓弦,张超,伊利亚斯·艾萨,时瑛,杨雪唯,努尔斯曼古丽奥斯曼,关亚群,徐书华. 2型糖尿病易感候选基因在世界不同人群中的多样性比较分析[J]. 遗传, 2016, 38(6): 543-559.
[13]	梁鑫, 张波, 刘苹, 翁土军, 张莉, 贺龙珠, 李芳菲, 屈晨, 王萍. FGFR2功能增强对小鼠下颌骨髁突发育影响[J]. 遗传, 2015, 37(6): 561-567.
[14]	张君, 张望强, 丁毓磊, 许彭, 王婷婷, 徐文静, 陆环, 刘宗智, 谢建新. 腹部脂肪组织APN基因DNA甲基化及mRNA表达与维吾尔族T2DM的相关性[J]. 遗传, 2015, 37(3): 269-275.
[15]	吴日,马超,李晓丹,段会坤,姬艳丽,王宇,姜苹哲,王海松,屠培培,李淼,尼钢钢,马百成,李明刚. 长效促胰岛素降糖酵母的构建及其对糖尿病模型小鼠的治疗效果[J]. 遗传, 2015, 37(2): 183-191.