Presumed missense and synonymous mutations in ATP7B gene cause exon skipping in Wilson disease

Abstract

Our results suggest that aberrant exon skipping associated to putative splicing enhancer disruption and silencer creation is one previously unrecognized mechanism in Wilson disease. What is more, the multiplex ligation-dependent probe amplification assay for the detection of exon deletions may be valuable in individuals with clinical Wilson disease diagnosis where one or no mutation has been identified by sequencing.

Whole‐exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype

“…28 However, direct sequencing conducted in 44 Chinese WD patients presented with hepatic manifestations identified a heterozygous mutation in 5 cases, of whom 3 patients appeared to be also carriers of large deletions found by the multiplex ligation-dependent probe amplification assay. 32 Thus, while the clinical usefulness of WES is unquestionable, our WES results were negative and inconclusive in three and 27 of WD patients, respectively. These negative and inconclusive results likely reflect challenges in distinguishing structural variation of the DNA sequence, including multiplication and heterozygous deletions.…”

“…While heterozygote carriers are often clinically asymptomatic, detailed examination may reveal subtle abnormalities . However, direct sequencing conducted in 44 Chinese WD patients presented with hepatic manifestations identified a heterozygous mutation in 5 cases, of whom 3 patients appeared to be also carriers of large deletions found by the multiplex ligation‐dependent probe amplification assay . Thus, while the clinical usefulness of WES is unquestionable, our WES results were negative and inconclusive in three and 27 of WD patients, respectively.…”

Genetics of Wilson disease and Wilson‐like phenotype in a clinical series from eastern Spain

“…We focused on investigating the consequences of six splicing mutations. Mostly, variants residing at splice site consensus sequences lead to single exon skipping, 6,7 as it occurs with c.1708‐1G>A and c.4124+5G>A. Exonic changes, such as c.4022G>T, can also cause exon skipping, 8 although they are usually presumed as changes on the protein. In occasions, a mutation located at the splice site can produce the inclusion of an intron fragment or the removal of an exon fragment because a nearby cryptic site is activated, 6,7 as it happens with c.4125‐1G>C and c.2447+1G>T. The c.2447+1G>T change only presented an altered splicing with the minigene approach, which could be caused by a non‐sense mediated decay (NMD) mechanism, because in the transcript analysis, only one allele was sequenced.…”

Only the tip of the Iceberg? Role of ATP7B‐exon skipping in Wilson disease

“…To date, these observations, as well as the heterogeneity in response to anti‐copper therapy, are still unexplained. In this respect, every study elucidating the molecular consequences of a distinct ATP7B mutation is of great significance: In the current issue of Liver International Wang et al turn our attention to exonic mutations resulting in aberrant “exon skipping” as a significant mechanism in WD.…”

“…In their article “Presumed Missense and Synonymous Mutations in ATP7B Gene Cause Exon Skipping in Wilson Disease” Wang et al identified four ATP7B mutations that have not been previously described. The identified mutations were analysis with bioinformatics prediction programs regarding for possible exonic splicing enhancers (ESE) disruption or exonic splicing silencer (ESS) creation.…”