Low-GGT intrahepatic cholestasis associated with biallelic USP53 variants: Clinical, histological and ultrastructural characterization
Low-GGT intrahepatic cholestasis associated with biallelic USP53 variants: Clinical, histological and ultrastructural characterization
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与双等位基因 USP53 变异相关的低 GGT 肝内胆汁淤积：临床、组织学和超微结构特征
DOI：
10.1111/liv.14422
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发表时间：
2020-04-07
影响因子：
6.7
通讯作者：
Wang, Jian-She
中科院分区：
文献类型：
--
作者：
Zhang, Jing;Yang, Ye;Wang, Jian-She
背景和目的 约 20% 的儿童患有胆汁淤积且血清 γ-谷氨酰转移酶 (GGT) 活性正常或较低，但尚未确定病因。我们寻找与儿科肝胆疾病有关的新基因。方法我们对 2011 年至 2018 年在我们中心进行评估的 69 名儿童进行了全外显子组测序，这些儿童患有低 GGT 胆汁淤积，并且在 ATP8B1、ABCB11、NR1H4、MYO5B 或 TJP2 中未发现纯合/复合杂合预测致病变异 (PPV)。回顾了临床记录以及肝活检材料的光学显微镜和透射电子显微镜检查结果。结果在来自七个无关家族的七名患者中，USP53中发现双等位基因PPV（总共10个），最近与肝内胆汁淤积相关。七个变体被归类为致病性：一个规范剪接，c.569 + 2T > C，以及六个无义或移码：c.169C > T (p.Arg57Ter)、c.581delA (p.Arg195GlufsTer38)、c.831_832insAG (p.Val279GlufsTer16)、 c.1012C > T (p.Arg338Ter)、c.1426C > T (p.Arg476Ter) 和 c.1558C > T (p.Arg520Ter)。其中三个可能致病：c.297G > T (p.Arg99Ser)、c.395A > G (p.His132Arg) 和 c.878G > T (p.Gly293Val)。所有患者的黄疸都是在年龄时开始的
Background & Aims In about 20% of children with cholestasis and normal or low serum gamma-glutamyltransferase (GGT) activity, no aetiology is identified. We sought new genes implicated in paediatric hepatobiliary disease.Methods We conducted whole-exome sequencing in 69 children evaluated at our centre from 2011 to 2018 who had low-GGT cholestasis and in whom homozygous/compound heterozygous predictedly pathogenic variants (PPVs) in ATP8B1, ABCB11, NR1H4, MYO5B or TJP2 were not found. Clinical records and findings on light microscopy and transmission electron microscopy of liver biopsy materials were reviewed.Results In seven patients from seven unrelated families, biallelic PPVs (10 in total) were found in USP53, recently associated with intrahepatic cholestasis. Seven variants were classified as pathogenic: one canonical splicing, c.569 + 2T > C, and six nonsense or frameshifting: c.169C > T (p.Arg57Ter), c.581delA (p.Arg195GlufsTer38), c.831_832insAG (p.Val279GlufsTer16), c.1012C > T (p.Arg338Ter), c.1426C > T (p.Arg476Ter) and c.1558C > T (p.Arg520Ter). Three were likely pathogenic: c.297G > T (p.Arg99Ser), c.395A > G (p.His132Arg) and c.878G > T (p.Gly293Val). In all patients, jaundice began at age