Characterization of ATP8B1 gene mutations and a hot-linked mutation found in Chinese children with progressive intrahepatic cholestasis and low GGT.

Objectives: The aim of the study was to elucidate the role and characteristics of ATP8B1 gene mutations in mainland Chinese children with progressive intrahepatic cholestasis and low gamma-glutamyltransferase (GGT).
Patients and Methods: Twenty-four children who presented with progressive intrahepatic cholestasis and low GGT were admitted to a tertiary pediatric hospital in eastern China from January 2004 to July 2007. Five children with homozygous or compound heterozygous ABCB11 gene mutations were excluded from the study. All encoding exons and their flanking areas of ATP8B1 gene were sequenced in the remaining 19 patients, in whom only 1 or no mutation of ABCB11 was found. Clinical features and liver histology obtained by reviewing the medical records were compared among patients with different genotypes.
Results: Nine mutations of ATP8B1 gene were found in 9 patients. All of them were novel except for mutations I694N and R952X. A linked P209T and IVS6+5G>T mutation was found in 4 of 9 patients, including 2 homozygotes and 2 heterozygotes. Giant cell transformation of hepatocytes was demonstrated in 1 of 6 patients with ATP8B1 mutations and 4 of 5 patients with ABCB11 mutations.
Conclusions: ATP8B1 gene mutations play an important role in Chinese patients with progressive intrahepatic cholestasis and low GGT. The linked mutation P209T and IVS6+5G>T is a hot mutation in the Chinese population. Histological examination may be helpful in differentiating familial intrahepatic cholestasis type 1 from bile salt export pump-related disease.