Exon-skipping due to bi-allelic splice site mutations in the neurodevelopmental disease gene LNPK

Homozygous loss-of-function mutations in LNPK, the gene encoding the endoplasmic reticulum-associated protein lunapark, have previously been linked to an autosomal recessive neurodevelopmental syndrome. Here, we describe an individual harboring compound heterozygous predicted splice site mutations with an overall matching phenotype. In cultured fibroblasts, these mutations result in a dearth of transcript and severe loss of protein, thereby establishing their likely pathogenicity. The underlying reduction in gene expression is due to the activation of the nonsense-mediated decay (NMD) pathway as a consequence of exon skipping rather than intron retention, leading to aberrant transcripts. We further demonstrate that cells from the affected individual and her mother exhibit a significant increase in transcript compared with a control cell line when treated with an inhibitor of NMD, suggesting potential genetic compensation. Together, this report describes disease-causing variants in LNPK and reveals their impact on transcription and mRNA stability.