ABCB4突变基因型与表型的相关性

翁宇航; 杨永峰

doi:10.3969/j.issn.1001-5256.2021.11.052

ABCB4突变基因型与表型的相关性

DOI: 10.3969/j.issn.1001-5256.2021.11.052

翁宇航,
杨永峰^,

南京中医药大学附属南京医院(南京市第二医院) 肝病科，南京 210003

基金项目:

国家自然科学基金 (81970454)

详细信息

通信作者:
杨永峰，yyf1997@163.com

中图分类号: R575
计量
- 文章访问数: 813
- HTML全文浏览量: 316
- PDF下载量: 80
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-17
- 录用日期: 2021-05-10
- 出版日期: 2021-11-20

Association between genotype and phenotype of ABCB4 gene mutation

Yuhang WENG,
Yongfeng YANG^,

Department of Hepatology, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine & The Second Hospital of Nanjing, Nanjing 210003, China

Research funding:

National Natural Science Foundation of China (81970454)

摘要

摘要: ABCB4相关疾病是由于基因突变引起胆汁分泌障碍的综合征，在临床上可以导致胆管损伤、门静脉高压和肝硬化等。近年来随着遗传学和基因测序技术的发展，越来越多的突变位点被人们所发现，然而考虑到该病较为复杂，突变的致病性和致病机制目前尚不明确；而且该病为罕见病，仅通过基础研究或临床资料单方面往往难以确定ABCB4突变致病性，因此亟需建立起ABCB4基因型与表型之间的相关性，在基础研究与临床实践中构建完善体系。
- ABCB4 /
- 基因型 /
- 表型 /
- 突变
Abstract: ABCB4-related disease is the syndrome of bile secretion disorder caused by gene mutations and can cause bile duct injury, portal hypertension, and liver cirrhosis in clinical practice. With the development of genetics and gene sequencing techniques in recent years, more and more mutation sites have been identified; however, since this is a relatively complex disease, the pathogenicity and pathogenic mechanism of mutations remain unclear. Meanwhile, since this disease is rare, it is difficult to determine the pathogenicity of ABCB4 mutations based on basic research or clinical data. Therefore, it is urgent to establish the association between ABCB4 genotypes and phenotypes and construct a complete system in basic research and clinical practice.
- ABCB4 /
- Genotype /
- Phenotype /
- Mutation

HTML全文

表 1 ABCB4突变功能分类及治疗

项目	严重缺陷	成熟障碍	活性降低	稳定性降低	意义未明
突变 (举例)	无义突变移码突变缺失突变	c.1621A＞T(p.I541F) c.1667T＞G(p.L556R) c.2564A＞T(p.Q855L)	c.1037G＞T(p.S346l) c.1069T＞C(p.F357L) c. 1605G＞A(p.G535D) c.2177C＞T(p.P726L) c.2324C＞T(p.T775M) c.2860G＞A(p.G954S) c.3228 A＞T (p.S1076C)	c.1270A＞G(p.T424A) c.1529A＞G (p.N510S)	c.1954A＞G(p.R652G) c.523A＞G(p.T175A)
潜在治疗 (与UDCA联用)		伴侣蛋白(例如环孢菌素A)	CFTR增强剂(例如依伐卡托)，核受体激动剂(例如贝特类药物)，他汀类	核受体激动剂(例如贝特类药物)，他汀类药物

下载: 导出CSV

表 2 ABCB4相关疾病临床表型及突变

项目	ICP	DILI	LPAC	PFIC3
起病时期	妊娠后期	用药相关	40岁以下	婴儿期晚期(30%)至成年期早期
突变类型	杂合	杂合	杂合	复合杂合，纯合
突变位点 (举例)	c.1529 A＞G(p.N510S) c.711A＞T(p.I237I) c.1954A＞G(p.R652G)	c.2290A＞C(p.I764L) c.3245T＞A(p.L1082Q)	c.523A＞G(p.T175A) c.1954A＞G(p.R652G) c.3203T＞A(p.V1068G) c.140G＞A(p.A47G)	c.1376A＞G(p.D459G) c.1769G＞A (p.R590Q) c.1621A＞T(p.I541F) c.1667T＞G(p.L556R) c.1270A＞G(p.T424A) c.1529A＞G(p.N510S)

下载: 导出CSV

参考文献(30)

[1]	STÄTTERMAYER AF, HALILBASIC E, WRBA F, et al. Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults[J]. J Hepatol, 2020, 73(3): 651-663. DOI: 10.1016/j.jhep.2020.04.036.
[2]	ZOLNERCIKS JK, ANDRESS EJ, NICOLAOU M, et al. Structure of ABC transporters[J]. Essays Biochem, 2011, 50(1): 43-61. DOI: 10.1042/bse0500043.
[3]	ROSMORDUC O, HERMELIN B, BOELLE PY, et al. ABCB4 gene mutations and primary sclerosing cholangitis[J]. Gastroenterology, 2004, 126(4): 1220-1222; author reply 1222-1223. DOI: 10.1053/j.gastro.2004.02.042.
[4]	KUBITZ R, BODE J, ERHARDT A, et al. Cholestatic liver diseases from child to adult: The diversity of MDR3 disease[J]. Z Gastroenterol, 2011, 49(6): 728-736. DOI: 10.1055/s-0031-1273427.
[5]	LUCENA JF, HERRERO JI, QUIROGA J, et al. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis[J]. Gastroenterology, 2003, 124(4): 1037-1042. DOI: 10.1053/gast.2003.50144.
[6]	BACQ Y, GENDROT C, PERROTIN F, et al. ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy[J]. J Med Genet, 2009, 46(10): 711-715. DOI: 10.1136/jmg.2009.067397.
[7]	JACQUEMIN E, CRESTEIL D, MANOUVRIER S, et al. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy[J]. Lancet, 1999, 353(9148): 210-211. DOI: 10.1016/S0140-6736(05)77221-4.
[8]	ZHANG W, LIN R, LU Z, et al. Phenotypic and molecular characteristics of children with progressive familial intrahepatic cholestasis in south China[J]. Pediatr Gastroenterol Hepatol Nutr, 2020, 23(6): 558-566. DOI: 10.5223/pghn.2020.23.6.558.
[9]	DELAUNAY JL, DURAND-SCHNEIDER AM, DOSSIER C, et al. A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3[J]. Hepatology, 2016, 63(5): 1620-1631. DOI: 10.1002/hep.28300.
[10]	GORDO-GILART R, ANDUEZA S, HIERRO L, et al. Functional rescue of trafficking-impaired ABCB4 mutants by chemical chaperones[J]. PLoS One, 2016, 11(2): e0150098. DOI: 10.1371/journal.pone.0150098.
[11]	TRAUNER M, FUCHS CD, HALILBASIC E, et al. New therapeutic concepts in bile acid transport and signaling for management of cholestasis[J]. Hepatology, 2017, 65(4): 1393-1404. DOI: 10.1002/hep.28991.
[12]	SCHNEIDER G, PAUS TC, KULLAK-UBLICK GA, et al. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy[J]. Hepatology, 2007, 45(1): 150-158. DOI: 10.1002/hep.21500.
[13]	DIXON PH, SAMBROTTA M, CHAMBERS J, et al. An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy[J]. Sci Rep, 2017, 7(1): 11823. DOI: 10.1038/s41598-017-11626-x.
[14]	WESTBROOK RH, DUSHEIKO G, WILLIAMSON C. Pregnancy and liver disease[J]. J Hepatol, 2016, 64(4): 933-945. DOI: 10.1016/j.jhep.2015.11.030.
[15]	ZOLLNER G, THUERINGER A, LACKNER C, et al. Alterations of canalicular ATP-binding cassette transporter expression in drug-induced liver injury[J]. Digestion, 2014, 90(2): 81-88. DOI: 10.1159/000365003.
[16]	GANNE-CARRIÉ N, BAUSSAN C, GRANDO V, et al. Progressive familial intrahepatic cholestasis type 3 revealed by oral contraceptive pills[J]. J Hepatol, 2003, 38(5): 693-694. DOI: 10.1016/s0168-8278(03)00049-7.
[17]	ZOLLNER G, THUERINGER A, LACKNER C, et al. Alterations of canalicular ATP-binding cassette transporter expression in drug-induced liver injury[J]. Digestion, 2014, 90(2): 81-88. DOI: 10.1159/000365003.
[18]	ROSMORDUC O, HERMELIN B, POUPON R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis[J]. Gastroenterology, 2001, 120(6): 1459-1467. DOI: 10.1053/gast.2001.23947.
[19]	ERLINGER S. Low phospholipid-associated cholestasis and cholelithiasis[J]. Clin Res Hepatol Gastroenterol, 2012, 36(Suppl 1): s36-s40. DOI: 10.1016/S2210-7401(12)70019-0.
[20]	POUPON R, ROSMORDUC O, BOËLLE PY, et al. Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: A study of 156 consecutive patients[J]. Hepatology, 2013, 58(3): 1105-1110. DOI: 10.1002/hep.26424.
[21]	JACQUEMIN E. Progressive familial intrahepatic cholestasis[J]. Clin Res Hepatol Gastroenterol, 2012, 36(Suppl 1): s26-s35. DOI: 10.1016/S2210-7401(12)70018-9.
[22]	FANG LJ, WANG XH, KNISELY AS, et al. Chinese children with chronic intrahepatic cholestasis and high γ-glutamyl transpeptidase: Clinical features and association with ABCB4 mutations[J]. J Pediatr Gastroenterol Nutr, 2012, 55(2): 150-156. DOI: 10.1097/MPG.0b013e31824ef36f.
[23]	SALEEM K, CUI Q, ZAIB T, et al. Evaluation of a novel missense mutation in ABCB4 gene causing progressive familial intrahepatic cholestasis type 3[J]. Dis Markers, 2020, 2020: 6292818. DOI: 10.1155/2020/6292818.
[24]	KHABOU B, MAHJOUB B, BARBU V, et al. Phenotypic variability in Tunisian PFIC3 patients harboring a complex genotype with a differential clinical outcome of UDCA treatment[J]. Clin Chim Acta, 2018, 486: 122-128. DOI: 10.1016/j.cca.2018.07.035.
[25]	SHARMA A, PODDAR U, AGNIHOTRY S, et al. Spectrum of genomic variations in Indian patients with progressive familial intrahepatic cholestasis[J]. BMC Gastroenterol, 2018, 18(1): 107. DOI: 10.1186/s12876-018-0835-6.
[26]	SCHATZ SB, JVNGST C, KEITEL-ANSELMO V, et al. Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset[J]. Hepatol Commun, 2018, 2(5): 504-514. DOI: 10.1002/hep4.1149.
[27]	DAWSON RJ, LOCHER KP. Structure of a bacterial multidrug ABC transporter[J]. Nature, 2006, 443(7108): 180-185. DOI: 10.1038/nature05155.
[28]	GORDO-GILART R, ANDUEZA S, HIERRO L, et al. Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity[J]. Gut, 2015, 64(1): 147-155. DOI: 10.1136/gutjnl-2014-306896.
[29]	GORDO-GILART R, HIERRO L, ANDUEZA S, et al. Heterozygous ABCB4 mutations in children with cholestatic liver disease[J]. Liver Int, 2016, 36(2): 258-267. DOI: 10.1111/liv.12910.
[30]	AVENA A, PUGGELLI S, MORRIS M, et al. ABCB4 variants in adult patients with cholestatic disease are frequent and underdiagnosed[J]. Dig Liver Dis, 2021, 53(3): 329-344. DOI: 10.1016/j.dld.2020.12.003.