Goel, A;
Raghupathy, V;
Amirtharaj, GJ;
Chapla, A;
Venkatraman, A;
Ramakrishna, B;
Ramachandran, A;
... Eapen, CE; + view all
(2017)
ADAMTS13 missense variants associated with defective activity and secretion of ADAMTS13 in a patient with non-cirrhotic portal hypertension.
Indian Journal of Gastroenterology
, 36
(5)
pp. 380-389.
10.1007/s12664-017-0786-9.
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Abstract
BACKGROUND: Non-cirrhotic intrahepatic portal hypertension (NCIPH) is characterized by thrombotic microangiopathy of the portal venous system, low ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13), and high vWF (von Willebrand factor) levels. This study aimed to screen for ADAMTS13 mutations, focusing on the CUB domain, in these patients. METHODS: Prospectively recruited NCIPH patients and healthy volunteers underwent tests for plasma vWF-ADAMTS13 balance. Sanger sequencing of the CUB domain of ADAMTS13 was done in a subset of the NCIPH patients, and the detected mutation was screened for in all the study participants. Next-generation sequencing of clinically relevant exome and liver immunostaining for ADAMTS13 was done in patients with detected ADAMTS13 mutation. RESULTS: Plasma vWF-ADAMTS13 balance was significantly altered in 24 NCIPH patients (Child's class A:23, B:1) as compared to 22 controls. On initial sequencing of the CUB domain (17 cases and 3 controls), one NCIPH patient showed a rare missense variant (SNV) at position c.3829C >T resulting in p.R1277W (rs14045669). Subsequent RFLP analysis targeted to the R1277W variant did not detect this in any other NCIPH patient, nor in any of the 22 controls. The NCIPH patient with the R1277W variant had severe ADAMTS13 deficiency, consistently high vWF, other missense SNVs in ADAMTS13, vWF, and complement genes. Immunostaining of his liver biopsy revealed globules of ADAMTS13 within stellate cells. CONCLUSIONS: We report missense variants in ADAMTS13, vWF, and complement genes in a patient with NCIPH who had decreased secretion and activity of ADAMTS13 protein. Further studies are needed in NCIPH patients in this regard.
| Type: | Article |
|---|---|
| Title: | ADAMTS13 missense variants associated with defective activity and secretion of ADAMTS13 in a patient with non-cirrhotic portal hypertension |
| Location: | India |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s12664-017-0786-9 |
| Publisher version: | http://doi.org/10.1007/s12664-017-0786-9 |
| Language: | English |
| Additional information: | © Indian Society of Gastroenterology 2017. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Complement system, Liver, Microangiopathy, Next generation sequencing, Non-cirrhotic portal fibrosis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10030626 |
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