Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 3

Gonzalès, Emmanuel; Spraul, Anne; Jacquemin, Emmanuel

doi:10.1038/ejhg.2013.188

Cited by 10 publications

(8 citation statements)

References 15 publications

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“…Nine PFIC3 patients, eight of whom were previously reported, were included in the present study (Table ). ABCB4 gene analysis was performed as described …”

Section: Methodsmentioning

confidence: 99%

A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3

et al. 2015

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Progressive familial intrahepatic cholestasis type 3 is caused by biallelic variations of ABCB4, most often ( 70%) missense. In this study, we examined the effects of 12 missense variations identified in progressive familial intrahepatic cholestasis type 3 patients. We classified these variations on the basis of the defects thus identified and explored potential rescue of trafficking-defective mutants by pharmacological means. Variations were reproduced in the ABCB4 complementary DNA and the mutants, thus obtained, expressed in HepG2 and HEK293 cells. Three mutants were either fully (I541F and L556R) or largely (Q855L) retained in the endoplasmic reticulum, in an immature form. Rescue of the defect, i.e., increase in the mature form at the bile canaliculi, was obtained by cell treatments with cyclosporin A or C and, to a lesser extent, B, D, or H. Five mutations with little or no effect on ABCB4 expression at the bile canaliculi caused a decrease (F357L, T775M, and G954S) or almost absence (S346I and P726L) of phosphatidylcholine secretion. Two mutants (T424A and N510S) were normally processed and expressed at the bile canaliculi, but their stability was reduced. We found no defect of the T175A mutant or of R652G, previously described as a polymorphism. In patients, the most severe phenotypes appreciated by the duration of transplant-free survival were caused by ABCB4 variants that were markedly retained in the endoplasmic reticulum and expressed in a homozygous status. Conclusion: ABCB4 variations can be classified as follows: nonsense variations (I) and, on the basis of current findings, missense variations that primarily affect the maturation (II), activity (III), or stability (IV) of the protein or have no detectable effect (V); this classification provides a strong basis for the development of genotype-based therapies.

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“…Nine PFIC3 patients, eight of whom were previously reported, were included in the present study (Table ). ABCB4 gene analysis was performed as described …”

Section: Methodsmentioning

confidence: 99%

A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3

et al. 2015

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“…Table S16) despite it having not been previously associated with any type of cancer. A variant with a deleterious effect on ATP8B1 may lead to ATP8B1-related diseases, such as progressive familial intrahepatic cholestasis [Gonzales et al, 2014], but should not increase the chances of developing BC. Thus, while our framework may be effective at prioritizing variants, only genes with previous association to a disease should be included in analyses similar to the present study to minimize falsely prioritized variants.…”

Section: Discussionmentioning

confidence: 99%

“…Initially, it was included in the list of prioritized HBOC genes provided by ENIGMA, but evidence for its association with HBOC is lacking in the published literature. Furthermore, it is not a known susceptibility gene for any type of cancer (mutations in ATP8B1 cause progressive familial intrahepatic cholestasis [Gonzales et al, 2014]) and is infrequently mutated in breast tumors in several studies (e.g., see Cancer Genome Atlas Network [2012]).…”

Section: Negative Controlmentioning

confidence: 99%

Prioritizing variants in complete Hereditary Breast and Ovarian Cancer (HBOC) genes in patients lacking knownBRCAmutations

Caminsky

Mucaki

Perri

et al. 2016

Preprint

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BRCA1 and BRCA2 testing for HBOC does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N=287), including noncoding and flanking sequences of ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51B, STK11, TP53, and XRCC2, identified 38,372 unique variants. We apply information theory (IT) to predict and prioritize non-coding variants of uncertain significance (VUS) in regulatory, coding, and intronic regions based on changes in binding sites in these genes. Besides mRNA splicing, IT provides a common framework to evaluate potential affinity changes in transcription factor (TFBSs), splicing regulatory (SRBSs), and RNA-binding protein (RBBSs) binding sites following mutation. We prioritized variants affecting the strengths of 10 splice sites (4 natural, 6 cryptic), 148 SRBS, 36 TFBS, and 31 RBBS. Three variants were also prioritized based on their predicted effects on mRNA secondary (2°) structure, and 17 for pseudoexon activation. Additionally, 4 frameshift, 2 in-frame deletions, and 5 stop-gain mutations were identified. When combined with pedigree information, complete gene sequence analysis can focus attention on a limited set of variants in a wide spectrum of functional mutation types for downstream functional and cosegregation analysis.

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“…gene and is currently called MDR3 deficiency. 42 Since the discovery of these genes, it has become evident that PFIC disorders represent a phenotypic continuum from mild to severe phenotypes of cholestasis. Of interest, patients with such genetic defects may be diagnosed later in life beyond childhood.…”

Section: Progressive Familial Intrahepatic Cholestasismentioning

confidence: 99%

Individualized Medicine in Gastroenterology and Hepatology

Stephens

Boardman

Lazaridis

2017

Mayo Clinic Proceedings

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After the completion of the Human Genome Project, there has been an acceleration in methodologies on sequencing nucleic acids (DNA and RNA) at a high precision and with ever-decreasing turnaround time and cost. Collectively, these approaches are termed next-generation sequencing and are already affecting the transformation of medical practice. In this symposium article, we highlight the current knowledge of the genetics of selected gastrointestinal tract and liver diseases, namely, inflammatory bowel disease, hereditary cholestatic liver disease, and familial colon cancer syndromes. In addition, we provide a stepwise approach to use next-generation sequencing methodologies for clinical practice with the goal to improve the diagnosis as well as management of and/or therapy of the chosen digestive diseases. This early experience of applying next-generation sequencing in the practice of gastroenterology and hepatology will delineate future best practices in the field, ultimately for the benefit of our patients.

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Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 3

Cited by 10 publications

References 15 publications

A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3

A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3

Prioritizing variants in complete Hereditary Breast and Ovarian Cancer (HBOC) genes in patients lacking knownBRCAmutations

Individualized Medicine in Gastroenterology and Hepatology

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