Dataset Information

A New Variant of an Old Itch: Novel Missense Variant in ABCB4 Presenting with Intractable Pruritus.

ABSTRACT: We report a novel homozygous missense variant in ABCB4 gene in a Yemeni child born to consanguineous parents, with a significant family history of liver disease-related deaths, resulting in a progressive familial intrahepatic cholestasis (PFIC) type 3 phenotype requiring liver transplantation for intractable pruritus.

SUBMITTER: Shankar S

PROVIDER: S-EPMC9077154 | biostudies-literature | 2022 Mar-Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A New Variant of an Old Itch: Novel Missense Variant in <i>ABCB4</i> Presenting with Intractable Pruritus.

Shankar Sahana S Pande Apurva A Geetha Thenral S TS Raichurkar Karthik K Sakpal Malikarjun M Lochan Rajiv R Asthana Sonal S

Journal of clinical and experimental hepatology 20210429 2

We report a novel homozygous missense variant in <i>ABCB4</i> gene in a Yemeni child born to consanguineous parents, with a significant family history of liver disease-related deaths, resulting in a progressive familial intrahepatic cholestasis (PFIC) type 3 phenotype requiring liver transplantation for intractable pruritus. ...[more]

PMID: 35535055

Similar Datasets

Project description:Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a hepatic disorder occurring predominantly in childhood and is difficult to diagnose. PFIC3, being a rare autosomal recessive disease, is caused by genetic mutations in both alleles of ABCB4, resulting in the disruption of the bile secretory pathway. The identification of pathogenic effects resulting from different mutations in ABCB4 is the key to revealing the internal cause of disease. These mutations cause truncation, instability, misfolding, and impaired trafficking of the MDR3 protein. Here, we reported a girl, with a history of intrahepatic cholestasis and progressive liver cirrhosis, with an elevated gamma-glutamyltransferase level. Genetic screening via whole exome sequencing found a novel homozygous missense mutation ABCB4:c.1195G>C:p.V399L, and the patient was diagnosed with PFIC3. Various computational tools predicted the variant to be deleterious and evolutionary conserved. For functional characterization studies, plasmids, encoding ABCB4 wild-type and selected established mutant constructs, were expressed in human embryonic kidney (HEK-293T) and hepatocellular carcinoma (HepG2) cells. In vitro expression analysis observed a reduced expression of mutant protein compared to wild-type protein. We found that ABCB4 wild type was localized at the apical canalicular membrane, while mutant p.V399L showed intracellular retention. Intracellular mistrafficking proteins usually undergo proteasomal or lysosomal degradation. We found that after treatment with proteasomal inhibitor MG132 and lysosomal inhibitor bafilomycin A1, MDR3 expression of V399L was significantly increased. A decrease in MDR3 expression of mutant V399L protein may be a result of proteasomal or lysosomal degradation. Pharmacological modulator cyclosporin A and intracellular low temperature (30°C) treatment significantly rescued both the folding defect and the active maturation of the mutant protein. Our study identified a novel pathogenic mutation which expanded the mutational spectrum of the ABCB4 gene and may contribute to understanding the molecular basis of PFIC3. Therefore, genetic screening plays a conclusive role in the diagnosis of rare heterogenic disorders like PFIC3.

Project description:IntroductionParaneoplastic pruritus is defined as pruritus that occurs before or during the natural evolution of a hematologic disease. The reported prevalence is 30% in patients with Hodgkin's lymphoma. The severity of this pruritus has a very negative impact on patients' quality of life. Very few studies have been made to examine the efficacy of pharmacological treatments for this type of pruritus. One drug that appears to be effective in this respect is off-label aprepitant, a neurokinin 1 receptor antagonist.Case presentationA 20-year-old Caucasian woman presented with lateral neck nodes, sweating, and pruritus and was diagnosed with stage IIB nodular sclerosis Hodgkin's lymphoma. Throughout this period during the disease the pruritus was ever-present. Improvement was achieved with some of the chemotherapy treatments, but the symptom returned when the various treatments were withdrawn due to disease progression or poor tolerance. In the middle of the seventh year, she was admitted to our hospital with uncontrolled pruritus that resulted in severe lesions due to scratching. In response, aprepitant (off-label) 80 mg/day was added to the chemotherapic treatment of the pruritus, after studying the various treatment options. She reported a score of 9 on a visual analogue scale for the pruritus, and a score of 3 on the Eastern Cooperative Oncology Group performance status scale of performance status. After two weeks of treatment with aprepitant, she reported a score of 5 on the visual analogue scale for the pruritus, and this improved to a score of 4 in a month, which allowed her to lead a better quality of life, with an Eastern Cooperative Oncology Group performance status score between 1 and 2.ConclusionsSeveral cases and case series have been reported on the use of aprepitant for paraneoplastic pruritus, but none have referred to its use for Hodgkin's lymphoma. A prospective study was carried out to evaluate the efficacy of this drug in refractory pruritus secondary to Sezary syndrome, and other authors have studied the effectiveness of aprepitant against pruritus, secondary to biological therapy with erlotinib. In our case report, treatment was started with daily doses of aprepitant 80 mg. Pruritus improvement appeared to be attributable exclusively to the administration of aprepitant.

Dataset Information

A New Variant of an Old Itch: Novel Missense Variant in ABCB4 Presenting with Intractable Pruritus.

Publications

A New Variant of an Old Itch: Novel Missense Variant in <i>ABCB4</i> Presenting with Intractable Pruritus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets