Novel missense mutation in VPS33B is associated with isolated low gamma-glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome
Novel missense mutation in VPS33B is associated with isolated low gamma-glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome
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VPS33B 中的新型错义突变与孤立性低 γ-谷氨酰转移酶胆汁淤积相关：关节弯曲、肾功能障碍和胆汁淤积综合征的减弱、不完整表型
DOI：
10.1002/humu.23770
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发表时间：
2019-09-03
期刊：
影响因子：
3.9
通讯作者：
Wang, Jian-She
中科院分区：
文献类型：
--
作者：
Qiu, Yi-Ling;Liu, Teng;Wang, Jian-She
关节旋转、肾功能障碍和胆汁淤积症(ARC)综合征的典型表型，顾名思义，包括三个主要症状，在VPS33B或VIPAS39上存在双等位基因突变。除ARC综合征外，低γ-谷氨酰转移酶(GGT)胆汁淤积症常提示不同严重程度的遗传性肝病，但有些仍未确诊。几种典型的多器官表现的单基因缺陷有时可能仅表现为肝功能障碍，如DGUOK缺陷和AGL缺陷。此前，报道了4例VPS33B突变病例，这些病例没有关节融合，或者症状不那么严重，寿命更长，表明孤立性肝病的ARC表型可能不完全。因此，我们回顾了我们中心所有确诊为VPS33B/VIPARS39缺陷的患者，发现了三例表现为孤立性低GGT胆汁淤积伴顽固性瘙痒的患者。与其他具有典型ARC表型的患者不同，这些患者没有其他两种典型特征，存活时间更长，并且分享了一个新的错义VPS33B突变c.1726T>；C，p.Cys576Arg，导致蛋白表达下降，并在体外取消了与VIPAS39的相互作用。我们的VPS33B/VIPAS39突变患者的血清胆汁酸谱显示出与胆盐输出泵原发性缺陷相似的变化，其中孤立胆汁淤积型患者的总次级胆汁酸水平高于典型ARC表型患者，表明VPS33B部分残留功能。
The typical phenotype of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome involves three cardinal symptoms as the name describes, harboring biallelic mutations on VPS33B or VIPAS39. Except for ARC syndrome, low gamma-glutamyltransferase (GGT) cholestasis often implies hereditary hepatopathy of different severity; however, some remain undiagnosed. Several monogenic defects typically with multiorgan manifestations may only present liver dysfunction at times, such as DGUOK defect and AGL defect. Previously, four VPS33B mutated cases were reported without arthrogryposis, or with less severe symptoms and longer lifespan, indicating the possibility of incomplete ARC phenotype of isolated hepatopathy. So we retrospectively reviewed all patients with confirmed VPS33B/VIPARS39 defect in our center and identified three presenting isolated low-GGT cholestasis with intractable pruritus. Distinguished from others with typical ARC phenotype, these patients did not suffer the other two typical characteristics, survived much longer, and shared a novel missense VPS33B variation c.1726T>C, p.Cys576Arg, causing declined protein expression and abolished interaction with VIPAS39 in-vitro. Serum bile acid profiles of our VPS33B/VIPAS39 mutated patients revealed similar changes to primary defect of bile salt export pump, among which those with isolated cholestasis phenotype had a higher level of total secondary bile acids than that with typical ARC phenotype, indicating the partial residual function of VPS33B.