Clinical features and molecular mechanism of infantile cholestasis caused by IFT122 gene variants
10.3760/cma.j.cn112140-20250812-00743
- VernacularTitle:IFT122基因变异致婴儿胆汁淤积症的临床特征及分子机制
- Author:
Jiaqi LI
1
;
Yan LI
;
Ruida HE
;
Jiayan FENG
;
Jianshe WANG
Author Information
1. 复旦大学附属儿科医院肝病中心，上海 201102
- Publication Type:Journal Article
- Keywords:
Cholestasis;
IFT122 gene;
Cranioectodermal dysplasia;
Ciliopathies
- From:
Chinese Journal of Pediatrics
2026;64(1):99-105
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the clinical characteristics of infantile cholestasis caused by IFT122 gene variants and the molecular mechanism underlying its impact on primary cilia.Methods:The clinical data of an infant with cholestasis from the Children′s Hospital of Fudan University in September 2022 were retrospectively analyzed. The whole-exome sequencing was performed to identify candidate variants, which were validated by Sanger sequencing in the family. Immortalized cell lines were generated using lentiviral infection, followed by immunofluorescence staining to assess the impact of the variants on primary cilia. Intergroup comparisons were performed using the independent sample t-test and Mann-Whitney U test .Results:The proband was a 4-month-old male infant presenting with jaundice, distinctive facial features, and sagittal craniosynostosis. Blood biochemistry indicated elevated direct bilirubin, total bile acids, and transaminases, with markedly increased γ-glutamyltransferase (GGT). Liver pathology demonstrated giant cell hepatitis with cholestasis and bile duct dysplasia. Genetic analysis identified compound heterozygous variants in IFT122 (NM_052989.3) gene c.88G>C (p.Ala30Pro) and c.240G>C (p.Trp80Cys), which co-segregated with the disease in the family. Immunofluorescence analysis demonstrated that the IFT122 gene compound heterozygous missense variants not only significantly reduced the proportion of cilia-positive cells but also led to aberrant ciliary localization of ADP-ribosylation factor-like protein 13B (ARL13B).In addition, ciliary deposition with phosphatidylinositol polyphosphate 5-phosphatase type Ⅳ (INPP5E) was reduced. All differences were statistically significant (all P<0.05). Conclusion:The compound heterozygous missense variants in IFT122 gene not only impair ciliogenesis but also disrupt the ciliary localization of ARL13B and INPP5E, ultimately resulting in high-GGT infantile cholestasis.
