Relationship between phenotype and genotype of ABCB11 deficiency in siblings and literature review / 中华儿科杂志

Objective@#To explore the relationship between genotype and phenotype of ABCB11 deficiency.@*Methods@#Clinical data of two siblings with ABCB11 deficiency were retrospectively analyzed. Related literature from PubMed, CNKI and Wangfang databases was reviewed to date (up to August 2017) with 'ABCB11 gene’ or 'bile salt export pump’, 'cholestasis’ and 'child’ as key words.@*Results@#The patients were siblings. Both of them presented as jaundice, pruritus and hepatosplenomegaly since 3 days after birth. Significant laboratory findings on admission of the older sister included high total bilirubin, 170 µmol/L;conjugated bilirubin, 115.8 µmol/L;alanine aminotransferase, 168 U/L;total bile acid 186.3 µmol/L and normal gamma-glutamyl transpeptidase. While routine laboratory data of the younger brother were as follows: total bilirubin, 148.8 µmol/L;conjugated bilirubin, 96.3 µmol/L;alanine aminotransferase, 232.8 U/L;total bile acid 226 µmol/L, and normal gamma-glutamyl transpeptidase.Both received ursodeoxycholic acid and fat-soluble vitamins. Liver pathology of the younger brother showed giant hepatocytes with ballooning degeneration, focal necrosis and intrahepatic cholestasis. Both the patients harbor the same compound heterozygous mutations in ABCB11 gene, c.145C>T (p.Q49X) and c.1510G>A (p.E504K). The sister is 9 years old now, with normal liver function. Jaundice faded around 3 months after birth, pruritus relieved at age 5, and medications was stopped since then. The brother progressed to liver failure after an operation on perianal abscess when he was 8-month-old, and received living-related liver transplantation when he was 9 month and 20 days old (from his mother). Now he is 1 year and 5 months old, with normal liver function. Both are under our follow-up. Literature review revealed 18 ABCB11 deficiency patients from 7 families who had apparent different prognoses, within each family the siblings had the same ABCB11 gene mutation. Seven cases relieved after ursodeoxycholic acid therapy and/or partial external biliary diversion, 5 received orthotopic liver transplantation, 2 developed hepatocellular carcinoma and 4 cases died in childhood.@*Conclusions@#The clinical manifestations of ABCB11 deficiency may vary greatly in patients carrying the same genotype, even in siblings. Patients should be managed in individualized maner.

A novel ABCB11 mutation in an Iranian girl with progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis is an autosomal recessive liver disorder caused by (biallelic) mutations in the ATP8B1 of ABCB11 gene. A nine‑year‑old girl with cholestasis was referred for genetic counseling. She had a family history of cholestasis in two previous expired siblings. Genetic analysis of the ABCB11 gene led to the identification of a novel homozygous mutation in exon 25. The mutation 3593‑ A > G lead to a missense mutation at the amino acid level (His1198Arg). This mutation caused PFIC2 due to abnormal function in the bile salt export pump protein (BSEP).

Significance of V444A polymorphism of ABCB11 gene in neonatal cholestasis / 中华实用儿科临床杂志

Objective To explore the association between one common variant in ABCB11-1331T ＞ C (V444A) and neonatal cholestasis.Methods One hundred and ninety-two children with neonatal cholestasis were enrolled as case group,and 196 healthy children were selected as healthy control group.The SNP site of V444A was tested by fluorescent quantitative PCR.Fisher's exact test was performed to detect the differences in allele and genotype distribution between the 2 groups.Wilcoxon rank-sum test was used to test the differences of total bilirubin,total bile acid,γ-glutamyl transpeptidase levels among the patients with different genotypes.Results TT,TC and CC genotypic distribution of V444A were not significantly different between patients and controls (P =0.530).The T allele in the case group accounted for 29.9％,in the healthy control group accounted for 26.3％,there was no significant difference between the 2 groups(OR =1.12,P =0.264).Total bilirubin,total bile acid,γ-glutamyl transpeptidase levels in patients with different genotypes of V444A were also not statistically different (all P ＞ 0.05).Conclusion Only V444A variant may have no impacts on neonatal cholestasis.

Genetic diagnosis of progressive familial intrahepatic cholestasis type 2 / 临床儿科杂志

Objectives To investigate the clinical features of progressive familial intrahepatic cholestasis type 2 (PFIC2) and to illustrate the importance of genetic diagnosis. Methods The mutations in 27 exons of ABCB11 encoding bile salt export pump (BSEP) were identiifed using polymerase chain reaction (PCR) and direct DNA sequencing in 6 children with suspected PFIC2. The pathogenicity of the newly identiifed mutations were predicted by SIFT, PolyPhen-2, SNPs&GO software. The clini-cal features and laboratory examinations were reviewed. Results Four disease-causing mutations, p.R928*, p.E554K, p.R575Q and p.Y337H were identiifed, and the last three mutations were novel. These three kinds of novel mutations can cause the disease. Two children with genetic diagnosis had such manifestations as onset within a month after birth, jaundice, hepatosplenomegaly, upset, increased levels of total bilirubin and direct bilirubin, GGT<100 U/L and high levels of total bile acid. Conclusions Genetic diagnosis is a potent tool for clinical diagnosis of PFIC2.

ABCB11 Gene Variation and Cholestatic Diseases / 实用儿科临床杂志

ABCB11 gene encodes bile salt export pump (BSEP).It is almost exclusively expressed in the canalicular microvilli of liver.It is the principal conveyor of bile acids from hepatocyte cytoplasm into bile canaliculus.It is clearly that BSEP defects can induce progressive familial intrahepatic cholestasis type 2 and benign recurrent intrahepatic cholestasis type 2.ABCB11 gene variation are also responsible for intrahepatic cholestasis of pregnancy,drug-induced cholestasis,primary sclerosis cholangitis and primary bile cirrhosis.This paper reviewed the association of ABCB11 gene variation and these diseases.