ArticleHuman mutation2021
Functional characterization of ABCC8 variants of unknown significance based on bioinformatics predictions, splicing assays, and protein analyses: Benefits for the accurate diagnosis of congenital hyperinsulinism.
Article in Human mutation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 9 citations in OpenAlex.
- Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes.The Journal of clinical endocrinology and metabolism · 2026Article
- Bayliss-Starling Prize Lecture: KThe Journal of physiology · 2025Article
- Genetically Proxied Antidiabetic Drug Target and Primary Open-Angle Glaucoma: A Mendelian Randomization Study.Health science reports · 2024Article
- The Changing Landscape of Neonatal Diabetes Mellitus in Italy Between 2003 and 2022.The Journal of clinical endocrinology and metabolism · 2024Article
- Neonatal hyperinsulinism with anWorld journal of clinical cases · 2023Article
- Personalized Therapeutics for KAnnual review of pharmacology and toxicology · 2023Review
- KFrontiers in endocrinology · 2023Review
- Evaluation in Monogenic Diabetes of the Impact ofHuman mutation · 2023Article
- Splicing Outcomes of 5' Splice Site GT>GC Variants That Generate Wild-Type Transcripts Differ Significantly Between Full-Length and Minigene Splicing Assays.Frontiers in genetics · 2021Article
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
ABCC8 encodes the SUR1 subunit of the β-cell ATP-sensitive potassium channel whose loss of function causes congenital hyperinsulinism (CHI). Molecular diagnosis is critical for optimal management of CHI patients. Unfortunately, assessing the impact of ABCC8 variants on RNA splicing remains very challenging as this gene is poorly expressed in leukocytes. Here, we performed bioinformatics analysis and cell-based minigene assays to assess the impact on splicing of 13 ABCC8 variants identified in 20 CHI patients. Next, channel properties of SUR1 proteins expected to originate from minigene-detected in-frame splicing defects were analyzed after ectopic expression in COSm6 cells. Out of the analyzed variants, seven induced out-of-frame splicing defects and were therefore classified as recessive pathogenic, whereas two led to skipping of in-frame exons. Channel functional analysis of the latter demonstrated their pathogenicity. Interestingly, the common rs757110 SNP increased exon skipping in our system suggesting that it may act as a disease modifier factor. Our strategy allowed determining the pathogenicity of all selected ABCC8 variants, and CHI-inheritance pattern for 16 out of the 20 patients. This study highlights the value of combining RNA and protein functional approaches in variant interpretation and reveals the minigene splicing assay as a new tool for CHI molecular diagnostics.
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