Compound heterozygous mutations of <i>ABCB11</i> responsible for benign recurrent intrahepatic cholestasis

Tai, Yang; Xie, Yan; Tang, Chaowei

doi:10.1111/1751-2980.12227

Cited by 3 publications

(2 citation statements)

References 11 publications

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“…Cholestatic liver diseases in older children or adults may also have a genetic basis, including several due to variants in genes often thought to be limited to a neonatal presentation of cholestasis. For example, variants in ABCB11 are associated with benign recurrent intrahepatic cholestasis (12,13), whereas ABCB4 variants have been associated with intrahepatic cholestasis of pregnancy, low phospholipid-associated cholelithiasis, and PFIC (14)(15)(16). Bile acid synthesis defects and ALGS also can present or be diagnosed in older children and adults (6,(17)(18)(19).…”

Section: What Is Newmentioning

confidence: 99%

Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults

Karpen

Kamath

Alexander

et al. 2021

Journal of Pediatric Gastroenterology &Amp; Nutrition

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Objectives: Cholestasis is caused by a wide variety of etiologies, often genetic in origin. Broad overlap in clinical presentations, particularly in newborns, renders prioritizing diagnostic investigations challenging. In this setting, a timely, comprehensive assessment using a multigene panel by a clinical diagnostic laboratory would likely prove useful. We summarize initial findings from a testing program designed to discover genetic causes of cholestasis. Methods: A neonatal/adult sequencing panel containing 66 genes (originally 57; nine added March 2017) relevant to cholestasis was used. A broad range of eligible patients were enrolled with current/history of cholestasis without an identified cause, or unexplained chronic liver disease. DNA sequencing utilized a custom-designed capture library, and variants were classified and reported as benign, likely benign, variant of unknown significance (VOUS), likely pathogenic (LP), or pathogenic (P), according to the clinical interpretation workflow at EGL Genetics (Tucker, GA). Results: A total of 2433 samples were submitted between February 2016 and December 2017; 2171 results were reported. Median turnaround time was 21 days. Results from the 2171 subjects (57% <1 year old) included 583 P variants, 79 LP variants, and 3117 VOUS; 166 P/LP variants and 415 VOUS were novel. The panel's overall diagnostic yield was 12% (n ¼ 265/ 2171) representing 32 genes. The top five genetic diagnoses for the group, in order: JAG1 þ NOTCH2 (Alagille syndrome), ABCB11, SERPINA1, ABCB4, and POLG. Conclusions: These findings support the utility of comprehensive rapid multigene testing in diagnosing cholestasis and highlight the evolving understanding of genetic variants contributing to the pathogenesis of cholestasis.

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Section: What Is Newmentioning

confidence: 99%

Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults

Karpen

Kamath

Alexander

et al. 2021

Journal of Pediatric Gastroenterology &Amp; Nutrition

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“…According to existing reports, the incidence of PISs is high in East Asia, and its incidence in Southern China is significantly higher than in Northern China; thus, it is believed that the incidence of PISs displays very strong regional and ethnic differences (1). The identified mutations in the ABCB11 gene lead to defects in BSEP protein expression that can cause changes in bile salt content (26), and it has been shown that mutations in this gene are associated with the pathogenesis of cholestasis (27–29). Therefore, the role of ABCB11 gene mutations in the pathogenesis of PISs was investigated.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of the correlation between ABCB11 gene mutation and primary intrahepatic stone

Gan

Cui

et al. 2018

Mol Med Report

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The adenosine 5′-triphosphate binding cassette subfamily B member (ABCB)11 gene is involved in bile transport, and mutations in this gene are associated with cholestasis and cholelithiasis. Therefore, the aim of the present study was to investigate the association between ABCB11 gene mutation and primary intrahepatic stone (PIS)s and to investigate the mechanism through which ABCB11 gene mutations affect the expression of the corresponding protein. Mutations of the ABCB11 gene in 443 PIS patients and 560 healthy participants were detected by exon sequencing. The expression levels of ABCB11 mRNA and bile salt export pump (BSEP) protein in the liver tissues of patients with PISs were measured by quantitative polymerase chain reaction and western blot analysis. The mutant plasmids constructed by site-directed mutagenesis of the human BSEP gene were transfected into human embryonic kidney 293 (293) cells and Madin-Darby canine kidney (MDCK) cells, and the expression and distribution of rs118109635 of BSEP was measured. There were two significant mutations in the ABCB11 gene of the PIS patients compared with the healthy population; a missense mutation, rs118109635 (P=0.025), and a synonymous mutation, rs497692 (P=0.006). The two mutations were associated with the occurrence of preoperative jaundice (P=0.026, and P=0.011, respectively). The expression levels of BSEP in PIS patients with the missense mutation rs118109635 was decreased, whereas its mRNA expression levels remained unchanged. In PIS patients with the synonymous mutation rs497692, the expression levels of ABCB11 were decreased at both the mRNA and protein level. It was also found that mutation A865V reduced the expression levels of BSEP in 293 cells at the cellular level; its distribution in MDCK cell membranes was decreased, whereas its mRNA levels remained unchanged. The mutated loci at rs118109635 and rs497692 of the ABCB11 gene were correlated with PISs, causing a decreased expression of BSEP and reduced distribution of the protein in the cell membrane. Therefore, mutations at rs118109635 and rs497692 of the ABCB11 gene may be risk factors for PISs.

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Bir çocukta İyi Huylu Tekrarlayan İntrahepatik Kolestaz tip 2: olgu sunumu ve yeni mutasyon

et al. 2020

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Compound heterozygous mutations of ABCB11 responsible for benign recurrent intrahepatic cholestasis

Cited by 3 publications

References 11 publications

Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults

Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults

Functional analysis of the correlation between ABCB11 gene mutation and primary intrahepatic stone

Bir çocukta İyi Huylu Tekrarlayan İntrahepatik Kolestaz tip 2: olgu sunumu ve yeni mutasyon

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