Bile Salt Export Pump Gene Mutations in Two Japanese Patients With Progressive Familial Intrahepatic Cholestasis

Goto, Kenji; Sugiyama, Kohachiro; Sugiura, Tetsuro; Ando, Tsutomu; Mizutani, Fumihiko; Terabe, Koji; Ban, Kyoko; Togari, Hajime

doi:10.1097/00005176-200305000-00012

Cited by 35 publications

(27 citation statements)

References 12 publications

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“…7,8,12,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][57][58][59] This study showed that some ABCB11 missense mutations were associated with splicing defects, most caused protein processing defects, and the two functionally analyzed showed a reduction in taurocholate transport. Additionally, the ability to modulate splicing and protein processing defects was examined; some mutations were amenable to such treatments.…”

Section: Discussionmentioning

confidence: 77%

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing

et al. 2008

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The gene encoding the human bile salt export pump (BSEP), ABCB11, is mutated in several forms of intrahepatic cholestasis. Here we classified the majority (63) of known ABCB11 missense mutations and 21 single-nucleotide polymorphisms (SNPs) to determine whether they caused abnormal ABCB11 pre-messenger RNA splicing, abnormal processing of BSEP protein, or alterations in BSEP protein function. Using an in vitro minigene system to analyze splicing events, we found reduced wild-type splicing for 20 mutations/SNPs, with normal mRNA levels reduced to 5% or less in eight cases. The common ABCB11 missense mutation encoding D482G enhanced aberrant splicing, whereas the common SNP A1028A promoted exon skipping. Addition of exogenous splicing factors modulated several splicing defects. Of the mutants expressed in vitro in CHO-K1 cells, most appeared to be retained in the endoplasmic reticulum and degraded. A minority had BSEP levels similar to wild-type. The SNP variant A444 had reduced levels of protein compared with V444. Treatment with glycerol and incubation at reduced temperature overcame processing defects for several mutants, including E297G. Taurocholate transport by two assessed mutants, N490D and A570T, was reduced compared with wild-type. Conclusion: This work is a comprehensive analysis of 80% of ABCB11 missense mutations and singlenucleotide polymorphisms at pre-mRNA splicing and protein processing/functional levels. We show that aberrant pre-mRNA splicing occurs in a considerable number of cases, leading to reduced levels of normal mRNA. Thus, primary defects at either the protein or the mRNA level (or both) contribute significantly to BSEP deficiency. These results will help to develop mutation-specific therapies for children and adults suffering from intrahepatic cholestasis due to BSEP deficiency. (HEPATOLOGY 2009;49:553-567.)

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Section: Discussionmentioning

confidence: 77%

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing

et al. 2008

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“…Different mutations in these genes have been identified in Asian population (11,12). The majority of them are different from those identified in other populations.…”

Section: Discussionmentioning

confidence: 91%

Investigation of Common Variations of ABCB4, ATP8B1 and ABCB11 Genes in Patients with Progressive Familial Intrahepatic Cholestasis

et al. 2017

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Background: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of hepatic disorders that can progress rapidly, leading to cirrhosis and death due to liver failure. Mutations and variations in three genes, including ATP8B1, ABCB11, and ABCB4, have been reported to be the main genetic cause of three subtypes of this disorder including PFIC1, PFIC2, and PFIC3, respectively. Objectives: Therefore, the aim of this study was to investigate more common mutations and variations associated with PFIC considering clinical and Para-clinical features of the disease. Methods: Thirty-five unrelated patients with PFIC from the south of Iran were selected randomly among all PFIC patients referring to Namazi hospital, affiliated to Shiraz University of Medical Sciences. Genomic DNA was extracted from the peripheral blood lymphocytes. Sequences related to these variations were then amplified by PCR in the 35 cholestasis patients and analyzed by Sanger® sequencing.

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“…To date, more than 100 mutations in ABCB11 have been identified [7,[10][11][12][13][14] ; however, genotype-phenotype correlations are not wholly clear. Severe phenotypes are often associated with mutations that lead to premature protein truncation or failure of protein production.…”

Section: Treepongkaruna S Et Al Pfic2 and Novel Abcb11 Mutationsmentioning

confidence: 99%

“…E297G and D482G are the two most common mutations in persons of European descent, and account for approximately 58% of BSEP mutations in European studies [7] . In Asian patients, few reports of mutations in PFIC type 2 exist [12][13][14] . Goto et al [14] have reported four mutations in ABCB11, predicted to yield V330X, R487H, R575X and E636G, in two Japanese PFIC patients.…”

Section: Treepongkaruna S Et Al Pfic2 and Novel Abcb11 Mutationsmentioning

confidence: 99%

“…In Asian patients, few reports of mutations in PFIC type 2 exist [12][13][14] . Goto et al [14] have reported four mutations in ABCB11, predicted to yield V330X, R487H, R575X and E636G, in two Japanese PFIC patients. Chen et al [13] have reported seven BSEP mutations (M183V, V284L, R303K, R487H, W493X, G1004D and 1145delC) in four PFIC patients of Chinese descent; none of these mutations has been described in Caucasian patients.…”

Section: Treepongkaruna S Et Al Pfic2 and Novel Abcb11 Mutationsmentioning

confidence: 99%

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Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis

Treepongkaruna¹,

Gaensan²,

Pienvichit³

et al. 2009

WJG

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Progressive familial intrahepatic cholestasis (PFIC) type 2 is caused by mutations in ABCB11 , which encodes bile salt export pump (BSEP). We report a Thai female infant who presented with progressive cholestatic jaundice since 1 mo of age, with normal serum γ-glutamyltransferase. Immunohistochemical staining of the liver did not demonstrate BSEP along the canaliculi, while multidrug resistance protein 3 was expressed adequately. Novel mutations in ABCB11 , a four-nucleotide deletion in exon 3, c.90_93delGAAA, and a single-nucleotide insertion in exon 5, c.249_250insT, were identified, with confirmation in her parents. These mutations were predicted to lead to synthesis of truncated forms of BSEP. Immunostaining and mutation analysis thus established the diagnosis of PFIC type 2.

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Bile Salt Export Pump Gene Mutations in Two Japanese Patients With Progressive Familial Intrahepatic Cholestasis

Abstract: Absence or presence of bile salt export protein gene mutations was confirmed as representing a useful prognostic marker for clinical course after liver transplantation.

Cited by 35 publications

References 12 publications

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing

Investigation of Common Variations of ABCB4, ATP8B1 and ABCB11 Genes in Patients with Progressive Familial Intrahepatic Cholestasis

Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis

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