Abstract：
TMEM67 (mecklin or MKS3) locates in the transition zone of cilia. Dysfunction of TMEM67 disrupts cilia-related signaling and leads to developmental defects of multiple organs in humans. Typical autosomal recessive TMEM67 defects cause partial overlapping phenotypes, including abnormalities in the brain, eyes, liver, kidneys, bones, and so forth. However, emerging reports of isolated nephronophthisis suggest the possibility of a broader phenotype spectrum. In this study, we analyzed the genetic data of cholestasis patients with no obvious extrahepatic involvement but with an unexplained high level of gamma-glutamyl transpeptidase (GGT). We identified five Han Chinese patients from three unrelated families with biallelic nonnull low-frequency TMEM67 variants. All variants were predicted pathogenic in silico, of which p. Arg820Ile and p. Leu144del were previously unreported. In vitro studies revealed that the protein levels of the TMEM67 variants were significantly decreased; however, their interaction with MKS1 remained unaffected. All the patients, aged 7-39 years old, had silently progressive cholestasis with elevated GGT but had normal bilirubin levels. Histological studies of liver biopsy of patients 1, 3, and 5 showed the presence of congenital hepatic fibrosis. We conclude that variants in TMEM67 are associated with a mild phenotype of unexplained, persistent, anicteric, and high GGT cholestasis without typical symptoms of TMEM67 defects; this possibility should be considered by physicians in gastroenterology and hepatology.
摘要：
TMEM67（mecklin或MKS3）位于纤毛的过渡区。TMEM67的功能障碍会破坏纤毛相关的信号，并导致人类多个器官的发育缺陷。典型的常染色体隐性TMEM67缺陷导致部分重叠表型，包括大脑的异常,眼睛,肝脏,肾脏，骨头,等等。然而,新出现的孤立的肾单位的报道表明，更广泛的表型谱的可能性。在这项研究中,我们分析了无明显肝外受累,但存在原因不明的高水平γ-谷氨酰转肽酶(GGT)的胆汁淤积患者的遗传数据.我们从三个不相关的家庭中鉴定出5名具有双等位基因非零低频TMEM67变异的汉族患者。所有变异都是电脑预测的致病性，其中p.Arg820Ile和p.Leu144del以前未报道。体外研究表明，TMEM67变体的蛋白质水平显着降低；然而，它们与MKS1的相互作用未受影响。所有的病人,7-39岁,轻度进行性胆汁淤积伴GGT升高，但胆红素水平正常。患者1、3和5的肝活检的组织学研究显示存在先天性肝纤维化。我们得出的结论是，TMEM67中的变体与无法解释的轻度表型有关，持久性,无黄疸,和高度GGT胆汁淤积，没有TMEM67缺陷的典型症状；这种可能性应该由胃肠病学和肝病学的医生考虑。
