ABCC8 – Monogenic Diabetes

ABCC8 encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic β-cell ATP-sensitive potassium (KATP) channel. Heterozygous and homozygous variants in ABCC8 are established causes of monogenic diabetes (MODY12) characterized by early-onset hyperglycemia and variable insulin secretory defects, supporting a definitive biological link between gene and disease.

1 Assess Clinical Validity

The gene–disease association is rated Strong based on pathogenic ABCC8 variants identified in 13 unrelated probands ([PMID:30734462], [PMID:31110826], [PMID:36407475], [PMID:27810688], [PMID:32418263]), segregation with diabetes in 19 affected relatives, and concordant functional studies demonstrating altered channel activity.

2 Genetic Evidence

Inheritance is Autosomal dominant with occasional recessive presentations. Segregation analysis showed 19 additional affected relatives harboring the familial variant. Case series and sequencing studies report at least 13 probands carrying missense and loss-of-function ABCC8 variants. The variant spectrum includes 11 missense substitutions and 2 truncating alleles. A recurrent hypomorphic variant, c.4055G>A (p.Arg1352His), was found in a young man with early-onset diabetes inherited from his mother ([PMID:31110826]).

3 Functional / Experimental Evidence

Functional assays in heterologous cells reveal that disease-associated SUR1 mutations reduce ATP sensitivity and/or impair channel trafficking. For example, channels containing SUR1-Y356C show a 4-fold decrease in ATP inhibition (IC₅₀ 95 µM vs 24 µM for wild type), leading to persistent channel opening and reduced insulin release ([PMID:18346985]). Pharmacological rescue with sulfonylureas restores surface expression and highlights the direct mechanistic link.

4 Conflicting Evidence

Certain ABCC8 mutations can cause opposite phenotypes: congenital hyperinsulinism in infancy versus diabetes later in life, indicating context-dependent effects and variable expressivity.

5 Integration & Conclusion

Genetic and functional data cohesively demonstrate that ABCC8 variants perturb KATP channel gating and β-cell excitability, causing monogenic diabetes. The identification of responsive variants supports genotype-guided sulfonylurea therapy. Further long-term follow-up may refine penetrance estimates in variant carriers.

Key Take-home: ABCC8 genetic testing is clinically actionable for diagnosis and precision treatment of monogenic diabetes.

References

• Pediatric diabetes • 2019 • Phenotypic variability in two siblings with monogenic diabetes due to the same ABCC8 gene mutation. PMID:30734462
• Case reports in genetics • 2019 • First Report of Diabetes Phenotype due to a Loss-of-Function ABCC8 Mutation Previously Known to Cause Congenital Hyperinsulinism. PMID:31110826
• Metabolism open • 2022 • Monogenic diabetes variants in Emirati women with gestational diabetes are associated with risk of non-autoimmune diabetes within 5 years after pregnancy. PMID:36407475
• Diabetes research and clinical practice • 2016 • Clinical whole exome sequencing in early onset diabetes patients. PMID:27810688
• Pediatric diabetes • 2020 • Neonatal diabetes due to potassium channel mutation: Response to sulfonylurea according to the genotype. PMID:32418263
• Diabetes • 2008 • A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults. PMID:18346985

Evidence Based Scoring (AI generated)