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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
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Functional characterization of inactivating ABCC8 variants causing congenital hyperinsulinism
Ping Wang1,2, Hong Liao2,3, Quyou Wang4
1Department of Medical Genetics/Prenatal Diagnostic Center, West China Second University Hospital, Sichuan University, Chengdu, China.
Clinical Genetics
|January 15, 2024
Summary
Congenital hyperinsulinism (CHI) is often caused by ABCC8 gene variants. This study found two ABCC8 variants that disrupt ATP-sensitive potassium channel function, leading to CHI by impairing protein transport and cellular response to glucose.
Area of Science:
- Genetics
- Molecular Biology
- Endocrinology
Background:
- Congenital hyperinsulinism (CHI) is a severe hypoglycemia disorder caused by persistent insulin secretion.
- Mutations in ABCC8 and KCNJ11 genes, encoding KATP channel subunits SUR1 and Kir6.2, are the most frequent causes of CHI.
Purpose of the Study:
- To investigate the functional impact of compound heterozygous ABCC8 variants (p.His103Tyr and p.Ile1105del) identified in an infant with CHI.
- To elucidate the mechanism by which these variants contribute to CHI pathogenesis.
Main Methods:
- Trio-whole-exome sequencing was performed to identify genetic variants.
- HEK293 and INS-1 cells were transfected with wild-type and variant ABCC8 plasmids to assess KATP channel trafficking and function.
- Intracellular calcium ([Ca2+]i) levels and glucose-stimulated responses were measured.
Main Results:
- Two compound heterozygous ABCC8 variants, p.His103Tyr and p.Ile1105del, were identified in a CHI patient.
- The p.Ile1105del and combined p.His103Tyr/p.Ile1105del variants impaired KATP channel trafficking to the plasma membrane.
- Channels formed by the variants exhibited elevated basal intracellular calcium and failed to respond to glucose stimulation.
Conclusions:
- The identified ABCC8 variants contribute to CHI through defective KATP channel trafficking and impaired function.
- These findings highlight the importance of KATP channel integrity in regulating insulin secretion and preventing hypoglycemia.
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