ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes

Al–Hussaini, Abdulrahman; Lone, Khurram; Bashir, Muhammed Salman; Alrashidi, Sami; Fagih, Mosa; Alanazi, Alanoud; AlYaseen, Salem; Almayouf, Abdulaziz; Alruwaithi, Muhanad; Asery, Ali

doi:10.1016/j.jpeds.2021.04.040

Cited by 14 publications

(22 citation statements)

References 15 publications

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“…Pruritus is often disproportionate to hyperbilirubinemia but correlates with the serum BA levels[ 1 ]. Symptoms begin in the first month of life in 15% of patients and by 3 mo of age in 61% of patients with PFIC1[ 12 ]. Undernutrition is generally responsible for poor growth.…”

Section: Familial Intrahepatic Cholestasis 1 Deficiencymentioning

confidence: 99%

“…It accounts for 37.5%-90.9% of cholestatic patients in the 9 studies that were analyzed in a systematic review[ 2 ]. Symptoms appear in the first month of life in 44% and by 3 mo of age in 72%[ 12 ]. Some patients with BSEP deficiency also present with early signs of vitamin D deficiency (rickets 3%-22%), vitamin K deficiency (bleeding 8%) or cholelithiasis (28%)[ 8 , 12 ].…”

Section: Bsep Deficiencymentioning

confidence: 99%

“…Symptoms appear in the first month of life in 44% and by 3 mo of age in 72%[ 12 ]. Some patients with BSEP deficiency also present with early signs of vitamin D deficiency (rickets 3%-22%), vitamin K deficiency (bleeding 8%) or cholelithiasis (28%)[ 8 , 12 ]. High serum alanine aminotransferase and alpha-fetoprotein levels, early liver failure, cholelithiasis, HCC, very low biliary BA concentration, and negative BSEP canalicular staining suggesting PFIC2 (Figures 2A and 2B )[ 12 ].…”

Section: Bsep Deficiencymentioning

confidence: 99%

“…Despite treatment, 76%-100% of PFIC2 continue to have pruritus with progression to severe liver disease and this may occur as early as 7 mo of age. Advanced portal and lobular fibrosis are seen in children beyond infancy[ 12 ]. Among patients undergoing LT, liver failure and/or HCC were detectable in about 60%.…”

Section: Bsep Deficiencymentioning

confidence: 99%

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Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

Alam¹,

Lal²

2022

WJH

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Recent evidence points towards the role of genotype to understand the phenotype, predict the natural course and long term outcome of patients with progressive familial intrahepatic cholestasis (PFIC). Expanded role of the heterozygous transporter defects presenting late needs to be suspected and identified. Treatment of pruritus, nutritional rehabilitation, prevention of fibrosis progression and liver transplantation (LT) in those with end stage liver disease form the crux of the treatment. LT in PFIC has its own unique issues like high rates of intractable diarrhoea, growth failure; steatohepatitis and graft failure in PFIC1 and antibody-mediated bile salt export pump deficiency in PFIC2. Drugs inhibiting apical sodium-dependent bile transporter and adenovirus-associated vector mediated gene therapy hold promise for future.

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Section: Familial Intrahepatic Cholestasis 1 Deficiencymentioning

confidence: 99%

Section: Bsep Deficiencymentioning

confidence: 99%

Section: Bsep Deficiencymentioning

confidence: 99%

Section: Bsep Deficiencymentioning

confidence: 99%

See 2 more Smart Citations

Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

Alam¹,

Lal²

2022

WJH

View full text Add to dashboard Cite

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“…There are three major proteins affected in PFIC, including the bile salt export pump (BSEP) encoded by ABCB11, multidrug resistance protein 3 (MDR3) encoded by ABCB4, and a membrane lipid composition protein (FIC1) encoded by ATP8B1, while three other reported proteins may be affected in PFIC patients, including tight junction protein 2 encoded by TJP2, the farnesoid X receptor (FXR) encoded by NR1H4, and myosin 5B encoded by MYO5B (Sambrotta et al, 2014;Qiu et al, 2017;Keitel et al, 2019). To date, except for NR1H4, splicing mutations have been found in other five genes associated with PFIC (http://www.hgmd.org) (Liu et al, 2010;van der Woerd et al, 2015;Khabou et al, 2016;Stenson et al, 2017;Al-Hussaini et al, 2021). In particular, FIC1 is part of the p-type adenosine triphosphatase type 4 subfamily involved in membrane phospholipid transport (Paulusma et al, 2008).…”

Section: Splicing Mutations Identified In Infantile Cholestasismentioning

confidence: 99%

RNA Splicing: A Versatile Regulatory Mechanism in Pediatric Liver Diseases

Zhou

Zhao

Wang

et al. 2021

Front. Mol. Biosci.

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With the development of high-throughput sequencing technology, the posttranscriptional mechanism of alternative splicing is becoming better understood. From decades of studies, alternative splicing has been shown to occur in multiple tissues, including the brain, heart, testis, skeletal muscle, and liver. This regulatory mechanism plays an important role in physiological functions in most liver diseases. Currently, due to the absence of symptoms, chronic pediatric liver diseases have a significant impact on public health. Furthermore, the progression of the disease is accelerated in children, leading to severe damage to their liver tissue if no precautions are taken. To this end, this review article summarizes the current knowledge of alternative splicing in pediatric liver diseases, paying special attention to liver damage in the child stage. The discussion of the regulatory role of splicing in liver diseases and its potential as a new therapeutic target is also included.

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Plastic structures for diverse substrates: A revisit of human ABC transporters

Hou

Wang

et al. 2022

Proteins

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ATP-binding cassette (ABC) superfamily is one of the largest groups of primary active transporters that could be found in all kingdoms of life from bacteria to humans. In humans, ABC transporters can selectively transport a wide spectrum of substrates across membranes, thus playing a pivotal role in multiple physiological processes. In addition, due to the ability of exporting clinic therapeutics, some ABC transporters were originally termed multidrug resistance proteins. Increasing investigations of human ABC transporters in recent years have provided abundant information for elucidating their structural features, based on the structures at distinct states in a transport cycle. This review focuses on the recent progress in human ABC structural analyses, substrate binding specificities, and translocation mechanisms. We dedicate to summarize the common features of human ABC transporters in different subfamilies, and to discuss the possibility to apply the fast-developing techniques, such as cryogenic electron microscopy, and artificial intelligence-assisted structure prediction, for future studies.

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ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes

Cited by 14 publications

References 15 publications

Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

RNA Splicing: A Versatile Regulatory Mechanism in Pediatric Liver Diseases

Plastic structures for diverse substrates: A revisit of human ABC transporters

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