Aagenaes 综合征/淋巴水肿胆汁淤积综合征 1 是由 UNC45A5'-非翻译区的一个创始变体引起的。

Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5'-untranslated region of UNC45A.

机构信息

Department of Pediatric Research, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Pb 4950, Nydalen, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Paediatrics, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Pb 4950, Nydalen, Oslo, Norway; European Reference Network - Rare Liver.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

出版信息

J Hepatol. 2023 Oct;79(4):945-954. doi: 10.1016/j.jhep.2023.05.037. Epub 2023 Jun 14.

DOI:10.1016/j.jhep.2023.05.037

PMID:37328071

Abstract

BACKGROUND & AIMS: Lymphedema cholestasis syndrome 1 or Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. The genetic background of this autosomal recessive disease was unknown up to now.

METHODS

A total of 26 patients with Aagenaes syndrome and 17 parents were investigated with whole-genome sequencing and/or Sanger sequencing. PCR and western blot analyses were used to assess levels of mRNA and protein, respectively. CRISPR/Cas9 was used to generate the variant in HEK293T cells. Light microscopy, transmission electron microscopy and immunohistochemistry for biliary transport proteins were performed in liver biopsies.

RESULTS

One specific variant (c.-98G>T) in the 5'-untranslated region of Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome. Nineteen were homozygous for the c.-98G>T variant and seven were compound heterozygous for the variant in the 5'-untranslated region and an exonic loss-of-function variant in UNC45A. Patients with Aagenaes syndrome exhibited lower expression of UNC45A mRNA and protein than controls, and this was reproduced in a CRISPR/Cas9-created cell model. Liver biopsies from the neonatal period demonstrated cholestasis, paucity of bile ducts and pronounced formation of multinucleated giant cells. Immunohistochemistry revealed mislocalization of the hepatobiliary transport proteins BSEP (bile salt export pump) and MRP2 (multidrug resistance-associated protein 2).

CONCLUSIONS

c.-98G>T in the 5'-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome.

IMPACT AND IMPLICATIONS

The genetic background of Aagenaes syndrome, a disease presenting with cholestasis and lymphedema in childhood, was unknown until now. A variant in the 5'-untranslated region of the Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome, providing evidence of the genetic background of the disease. Identification of the genetic background provides a tool for diagnosis of patients with Aagenaes syndrome before lymphedema is evident.

摘要

背景与目的

淋巴水肿性胆汁淤积综合征 1 型或 Aagenaes 综合征是一种以新生儿胆汁淤积、淋巴水肿和巨细胞肝炎为特征的疾病。这种常染色体隐性疾病的遗传背景至今尚不清楚。

方法

共对 26 例 Aagenaes 综合征患者和 17 名父母进行了全基因组测序和/或 Sanger 测序。PCR 和 Western blot 分析分别用于评估 mRNA 和蛋白水平。CRISPR/Cas9 用于在 HEK293T 细胞中产生变异。对肝活检进行了胆管转运蛋白的光镜、透射电镜和免疫组织化学检查。

结果

在所有测试的 Aagenaes 综合征患者中均发现 Unc-45 肌球蛋白伴侣 A（UNC45A）5'非翻译区的特定变异（c.-98G>T）。19 例为 c.-98G>T 变异纯合子，7 例为 5'非翻译区变异和 UNC45A 外显子缺失功能变异的复合杂合子。Aagenaes 综合征患者 UNC45A mRNA 和蛋白表达水平低于对照组，这在 CRISPR/Cas9 构建的细胞模型中得到了重现。新生儿期的肝活检显示胆汁淤积、胆管稀少和多核巨细胞形成明显。免疫组织化学显示胆盐输出泵（BSEP）和多药耐药相关蛋白 2（MRP2）的肝肠转运蛋白定位错误。

结论

UNC45A 5'非翻译区的 c.-98G>T 是 Aagenaes 综合征的致病遗传变异。

影响与意义

直到现在，一种以儿童期胆汁淤积和淋巴水肿为特征的疾病 Aagenaes 综合征的遗传背景尚不清楚。在所有测试的 Aagenaes 综合征患者中，均发现了 Unc-45 肌球蛋白伴侣 A（UNC45A）5'非翻译区的变异，为该疾病的遗传背景提供了证据。遗传背景的确定为在淋巴水肿出现之前对 Aagenaes 综合征患者进行诊断提供了工具。