Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing
| Autor: | Marco Seri, Giovanni Vitale, Vilma Mantovani, Robert B. Russell, Ranka Vukotic, Antonietta D'Errico, Alessandro Mattiaccio, Pietro Andreone, Stefano Gitto, Francesco Raimondi |
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| Přispěvatelé: | DIPARTIMENTO DI MEDICINA SPECIALISTICA, DIAGNOSTICA E SPERIMENTALE, DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, Facolta' di MEDICINA e CHIRURGIA, Da definire, AREA MIN. 06 - Scienze mediche, Vitale, Giovanni, Gitto, Stefano, Raimondi, Francesco, Mattiaccio, Alessandro, Mantovani, Vilma, Vukotic, Ranka, D’Errico, Antonietta, Seri, Marco, Russell, Robert B., Andreone, Pietro, Vitale, G., Gitto, S., Raimondi, F., Mattiaccio, A., Mantovani, V., Vukotic, R., D'Errico, A., Seri, M., Russell, R. B., Andreone, P. |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Proband Genetic variants medicine.disease_cause Gastroenterology 0302 clinical medicine Pathogenic mutations ABCB11 Genetic variant ATP Binding Cassette Transporter Subfamily B Member 11 Oligonucleotide Array Sequence Analysis Adenosine Triphosphatases Mutation Cholestasis Bioinformatics analysi Progressive familial intrahepatic cholestasis Middle Aged ABCB4 Liver Elasticity Imaging Techniques Female 030211 gastroenterology & hepatology Adult Steroid Metabolism Inborn Errors medicine.medical_specialty Bioinformatics analysis Cryptogenic disease ATP Binding Cassette Transporter Subfamily B Adolescent Context (language use) Cholestasis Intrahepatic Zonula Occludens-2 Protein Progressive familial intrahepatic cholestasi Young Adult 03 medical and health sciences Internal medicine medicine Humans Pathogenic mutation business.industry Pruritus medicine.disease 030104 developmental biology business |
| Popis: | none 10 si First Online: 13 December 2017 Background: Mutations in ATP-transporters ATPB81, ABCB11, and ABCB4 are responsible for progressive familial intrahepatic cholestasis (PFIC) 1, 2 and 3, and recently the gene for tight junction protein-2 (TJP2) has been linked to PFIC4. Aim: As these four genes have been poorly studied in young people and adults, we investigated them in this context here. Methods: In patients with cryptogenic cholestasis, we analyzed the presence of mutations by high-throughput sequencing. Bioinformatics analyses were performed for mechanistic and functional predictions of their consequences on biomolecular interaction interfaces. Results: Of 108 patients, 48 whose cause of cholestasis was not established were submitted to molecular analysis. Pathogenic/likely pathogenic mutations were found in ten (21%) probands for 13 mutations: two in ATP8B1, six in ABCB11, two in ABCB4, three in TJP2. We also identified seven variants of uncertain significance: two in ATP8B1, one in ABCB11, two in ABCB4 and two in TJP2. Finally, we identified 11 benign/likely benign variants. Patients with pathogenic/likely pathogenic mutations had higher levels of liver stiffness (measured by FibroScan®) and bile acids, as well as higher rates of cholestatic histological features, compared to the patients without at least likely pathogenic mutations. The multivariate analysis showed that itching was the only independent factor associated with disease-causing mutations (OR 5.801, 95% CI 1.244â27.060, p = 0.025). Conclusions: Mutations in the genes responsible for PFIC may be involved in both young and adults with cryptogenic cholestasis in a considerable number of cases, including in heterozygous status. Diagnosis should always be suspected, particularly in the presence of itching. none Vitale, Giovanni; Gitto, Stefano; Raimondi, Francesco; Mattiaccio, Alessandro; Mantovani, Vilma; Vukotic, Ranka; D’Errico, Antonietta; Seri, Marco; Russell, Robert B.; Andreone, Pietro Vitale, Giovanni; Gitto, Stefano; Raimondi, Francesco; Mattiaccio, Alessandro; Mantovani, Vilma; Vukotic, Ranka; D’Errico, Antonietta; Seri, Marco; Russell, Robert B.; Andreone, Pietro |
| Databáze: | OpenAIRE |
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