ABCMdb

PMID: 19177487

Mullenbach R, Lammert F
The transporter "variome": the missing link between gene variants and bile salt transporter function.
Hepatology. 2009 Feb;49(2):352-4., [PubMed]

Sentences

No. Mutations Sentence Comment

24 ABCB11 p.Asp482Gly The results of the present study are consistent with data from recent high-throughput sequencing of transcripts, demonstrating that exon skipping is the most prevalent form of alternative splicing.12 This type of analysis also explains why some transporter variants that may appear to have rather low impact on the protein level, such as p.D482G,13 one of the most common PFIC missense mutations in Europe, give rise to a comparatively severe phenotype: The authors describe how this variant leads to altered pre-mRNA splicing, resulting in an mRNA which, when translated, introduces 14 novel amino acids, followed by a stop codon. Login to comment 25 ABCB11 p.Asp482Gly This represents a much more serious alteration than the replacement of one amino acid, and the severity of the splice-induced abnormality explains the almost complete lack of detectable BSEP protein in immunohistochemical analysis of livers from patients with the p.D482G mutation.13,14 Of note, a patient with obstetric cholestasis carrying this variant also displayed a severe phenotype resolving only in part after delivery.3 Additional weight is added to the results from the splice site analyses by the fact that the development of hepatocellular carcinoma and cholangiocarcinoma is highly associated with splice site changes, deletions, insertions, and nonsense mutations predicted to result in total absence of BSEP protein. Login to comment 33 ABCB11 p.Ile498Thr The resulting changes in protein structure can cause: (1) Functional impairment at the respective site of function (i.e., at the canalicular membrane) without detectable reduction (as seen in ABCB11 p.I498T). Login to comment 34 ABCB11 p.Val284Leu ABCB11 p.Ala588Val (2) Retention and degradation of the protein in the endoplasmatic reticulum (trafficking mutant, for example ABCB11 variants p.V284L and p.A588V). Login to comment 36 ABCB11 p.Asp482Gly (4) Generation of a novel splice donor or acceptor site by an exonic variant may create exon skipping or missplicing, thereby creating a premature stop codon (as seen in ABCB11 p.D482G) or generating instable mRNA species. Login to comment