Abstract:

Objective To identify KIF12 mutation in an infant with progressive familial intrahepatic cholestasis 8 (PFIC8) and to explore the functional consequences of the mutation. Methods The clinical data of the infant with PFIC8 were analyzed, and whole exome sequencing was conducted on the patient and his parents, and the variation was verified by Sanger sequencing. Immunofluorescence staining, cell phenotyping, qPCR and Western blotting were utilized to investigate the effect of the causative mutations on the gene functions. At the same time, the clinical data and gene variation of 17 reported PFIC8 patients were reviewed. Results The proband, a male infant aged one month and 14 days, exhibited symptoms of fever and jaundice. Whole exome sequencing showed that the KIF12 gene of the patient had a compound heterozygous mutation of c.539G>A+c.928C>T, which had not been reported before. Immunofluorescence staining of liver sections from the patient suggested that the mutation altered the subcellular localization of KIF12 protein within hepatocytes. In 293 T cells, phenotyping of the mutants revealed that c.539A, c.928T and c.539A+c.928T resulted in decreased mRNA levels of KIF12, while c.928T and c.539A+c.928T reduced the protein expression levels of KIF12. A review of the literature revealed seven single site mutations of KIF12 and a compound heterozygous mutation (c.538C>T+c.539G>A) that have been reported. Existing data indicated that the types of KIF12 mutations were not correlated with the extrahepatic clinical phenotypes of PFIC8 patients. Conclusions A novel compound heterozygous mutation was identified in an infant with PFIC8. Among the nine KIF12 mutations identified to date, the mutation types were not associated with the extrahepatic clinical phenotypes of PFIC8.

Key words: progressive familial intrahepatic cholestasis 8, KIF12 gene, whole exome sequencing, compound heterozygous mutation