KIF12基因新复合杂合突变导致进行性家族性肝内胆汁淤积1例报告

doi:10.12372/jcp.2024.24e0378

摘要/Abstract

摘要：

目的鉴定导致1例进行性家族性肝内胆汁淤积8（PFIC8）患儿的KIF12基因变异及其对功能的影响。方法分析1例PFIC8患儿的临床资料，对患儿及其父母进行全外显子组测序，变异用一代测序进行验证。通过免疫荧光染色、细胞模型、实时定量聚合酶链式反应和蛋白质免疫印迹反应研究变异对基因功能的影响。同时对已报道的17例PFIC8患儿的临床资料和基因变异进行文献复习。结果患儿，男，1个月14天，临床表现以发热和黄疸为主。全外显子组测序发现，患儿的KIF12基因存在c.539G>A+c.928C>T复合杂合突变，此前未见报道。免疫荧光结果显示患儿肝细胞的KIF12蛋白的细胞内定位发生改变。在293T细胞中，c.539A、c.928T和c.539A+c.928T均可以使KIF12的mRNA表达减少，c.928T和c.539A+c.928T可使KIF12的蛋白水平表达降低（P<0.05）。文献回顾显示，已有7个KIF12的纯合突变和1个复合杂合突变（c.538C>T+c.539G>A）被报道。在已报道的病例中，KIF12的突变类型和PFIC8患儿的肝外临床表型无关。结论在1例PFIC8患儿中发现1种新的KIF12复合杂合突变。在已发现的9个突变中，其类型与PFIC8肝外临床表型可能无关。

关键词: 进行性家族性肝内胆汁淤积8, KIF12基因, 全外显子组测序, 复合杂合突变

Abstract:

Objective To identify KIF12 mutation in an infant with progressive familial intrahepatic cholestasis 8 (PFIC8) and to explore the functional consequences of the mutation. Methods The clinical data of the infant with PFIC8 were analyzed, and whole exome sequencing was conducted on the patient and his parents, and the variation was verified by Sanger sequencing. Immunofluorescence staining, cell phenotyping, qPCR and Western blotting were utilized to investigate the effect of the causative mutations on the gene functions. At the same time, the clinical data and gene variation of 17 reported PFIC8 patients were reviewed. Results The proband, a male infant aged one month and 14 days, exhibited symptoms of fever and jaundice. Whole exome sequencing showed that the KIF12 gene of the patient had a compound heterozygous mutation of c.539G>A+c.928C>T, which had not been reported before. Immunofluorescence staining of liver sections from the patient suggested that the mutation altered the subcellular localization of KIF12 protein within hepatocytes. In 293 T cells, phenotyping of the mutants revealed that c.539A, c.928T and c.539A+c.928T resulted in decreased mRNA levels of KIF12, while c.928T and c.539A+c.928T reduced the protein expression levels of KIF12. A review of the literature revealed seven single site mutations of KIF12 and a compound heterozygous mutation (c.538C>T+c.539G>A) that have been reported. Existing data indicated that the types of KIF12 mutations were not correlated with the extrahepatic clinical phenotypes of PFIC8 patients. Conclusions A novel compound heterozygous mutation was identified in an infant with PFIC8. Among the nine KIF12 mutations identified to date, the mutation types were not associated with the extrahepatic clinical phenotypes of PFIC8.

Key words: progressive familial intrahepatic cholestasis 8, KIF12 gene, whole exome sequencing, compound heterozygous mutation

裴皓月, 龚一鸣, 韩心如, 白美荣, 褚迅, 周莹. KIF12基因新复合杂合突变导致进行性家族性肝内胆汁淤积1例报告[J]. 临床儿科杂志, 2024, 42(9): 791-797.

PEI Haoyue, GONG Yiming, HAN Xinru, BAI Meirong, CHU Xun, ZHOU Ying. A novel compound heterozygous mutation in KIF12 causing progressive familial intrahepatic cholestasis: a case report[J]. Journal of Clinical Pediatrics, 2024, 42(9): 791-797.

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表1

PFIC8患儿18例的基因型和临床表型"

患儿	变异位点	蛋白改变	突变方式	国家/民族	出现症状时年龄	肝脏表型	肝外表型	是否肝移植	参考文献
例1	c.463C>T	R155*	纯合	沙特阿拉伯	4个月	胆汁淤积，高GGT	－	－	[4]
例2	c.482-4_500del	－	纯合	阿富汗	8周	胆汁淤积，高GGT，肝纤维化	瘙痒	肝移植（4岁）	[13]
例3	c.482-7_500del	－	纯合	巴基斯坦	2周	胆汁淤积，高GGT	杵状指	－	[16]
例4	c.482-7_500del	－	纯合	巴基斯坦	7个月	胆汁淤积，高GGT	瘙痒	－	[16]
例5	c.538C>T, c.539G>A	R180W, R180Q	复合杂合	中国	出生时	胆汁淤积，高GGT	脾肿大，胃食管静脉曲张出血	肝移植（6.5岁）	[15]
例6	c.610G>A	V204M	纯合	土耳其	2个月	胆汁淤积，高GGT	右肾盆腔前后直径轻度增大	－	[3]
例7	c.610G>A	V204M	纯合	土耳其	9岁	胆汁淤积，高GGT	左肾扩张，脾肿大	－	[3]
例8	c.610G>A	V204M	纯合	沙特阿拉伯	14个月	胆汁淤积，高GGT，硬化性胆管炎	－	－	[4]
例9	c.610G>A	V204M	纯合	沙特阿拉伯	6个月	胆汁淤积，高GGT	－	肝移植（10个月）	[4]
例10	c.655C>T	R219*	纯合	叙利亚	1个月	胆汁淤积，高GGT	左肾积水	－	[3]
例11	c.655C>T	R219*	纯合	库尔德	11个月	胆汁淤积，高GGT，肝纤维化，胆管增生	瘙痒	肝移植（12岁）	[13]
例12	c.655C>T	R219*	纯合	库尔德	15个月	胆汁淤积，高GGT，胆管增生，肝纤维化，肝硬化	胰腺脂肪过多症	－	[13]
例13	c.655C>T	R219*	纯合	伊拉克	4周	胆汁淤积，高GGT	维生素K缺乏性出血，偏瘫	－	[13]
例14	c.655C>T	R219*	纯合	伊拉克	6周	胆汁淤积，高GGT，肝纤维化，胆管增生		等待肝移植	[13]
例15	c.655C>T	R219*	纯合	叙利亚	12岁	胆汁淤积，高GGT，胆管增生，肝硬化	脾肿大，血小板减少，白细胞减少	－	[13]
例16	c.656G>A	R219Q	纯合	沙特阿拉伯	5岁	胆汁淤积，高GGT	－	肝移植（6岁）	[4]
例17	c.659G>A	R220Q	纯合	印度	2周	胆汁淤积，高GGT	瘙痒，脾肿大	等待肝移植	[17]
例18 （本例）	c.539G>A, c.928C>T	R180Q, R310*	复合杂合	中国	1个月 14天	胆汁淤积，高GGT	－	－	－

表1

参考文献 20

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