Dataset Information

A novel MPV17 gene mutation in a Saudi infant causing fatal progressive liver failure.

ABSTRACT: We describe in this report the clinical, biochemical, and molecular features of a Saudi infant with hepatocerebral MDS secondary to a novel homozygous mutation in the MPV17 gene. An automated sequencing of the nuclear MPV17 gene was performed. The coding region (7 exons) of the MPV17 gene was amplified using an M13-tagged intronic primer and screened by direct sequencing of the PCR-amplified products (GenBank Association Number NM_002437.4). The sequencing of the entire coding region and intron-exon boundaries of MPV17 gene revealed a single homozygous variant, -c.278A > C(p.Q93P), which predicts the substitution of a highly conserved amino acid. This particular sequence variant has not been previously reported as a single-nucleotide polymorphism (SNP) or pathogenic mutation. Diagnostic workup for neonatal liver disorders should include mutation screening for known genes. The new advances in molecular genetics can help clinicians establish the diagnosis in a timely fashion, which may prevent a child from undergoing invasive and expensive investigations.

SUBMITTER: Sarkhy AA

PROVIDER: S-EPMC6074855 | biostudies-literature | 2014 Mar-Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel MPV17 gene mutation in a Saudi infant causing fatal progressive liver failure.

Sarkhy Ahmed Al AA Al-Sunaid Areej A Abdullah Ahmad A AlFadhel Majid M Eiyad Wafa W

Annals of Saudi medicine 20140301 2

We describe in this report the clinical, biochemical, and molecular features of a Saudi infant with hepatocerebral MDS secondary to a novel homozygous mutation in the MPV17 gene. An automated sequencing of the nuclear MPV17 gene was performed. The coding region (7 exons) of the MPV17 gene was amplified using an M13-tagged intronic primer and screened by direct sequencing of the PCR-amplified products (GenBank Association Number NM_002437.4). The sequencing of the entire coding region and intron- ...[more]

PMID: 24894789

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.

Dataset Information

A novel MPV17 gene mutation in a Saudi infant causing fatal progressive liver failure.

Publications

A novel MPV17 gene mutation in a Saudi infant causing fatal progressive liver failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure