2. Academic Validation
  3. Exon-skipping due to bi-allelic splice site mutations in the neurodevelopmental disease gene LNPK

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

  • HGG Adv. 2025 Nov 6;7(1):100543. doi: 10.1016/j.xhgg.2025.100543.
Rose M Doss 1,  Sara A Wirth 1,  Jonathan W Pitsch 1,  Caroline M Dias 2,  Andrea L Gropman 3,  Martin W Breuss 4
Affiliations

Affiliations

  • 1 Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • 2 Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Pediatrics, Section of Developmental Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • 3 Division of Neurogenetics and Neurodevelopmental Pediatrics, Children's National Health System, Washington, DC 20010, USA; Department of Neurology, George Washington University, Washington, DC 20037, USA; Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: [email protected].
PMID: 41204669 DOI: 10.1016/j.xhgg.2025.100543
Abstract

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.

Keywords

KIAA1715; LNPK; genetic compensation; lunapark; neurodevelopmental disorder; nonsense-mediated decay; splice site mutations.

Figures
Products