ABCC8 – Permanent Neonatal Diabetes Mellitus

Permanent neonatal diabetes mellitus (PNDM) is a rare monogenic disorder presenting within the first 6 months of life. ABCC8 encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic β-cell ATP-sensitive potassium (KATP) channel. Activating variants in ABCC8 cause increased channel activity, reduced ATP sensitivity, and impaired insulin secretion, resulting in lifelong hyperglycemia ([PMID:24843665]).

Genetic evidence for ABCC8 in PNDM is robust. Over 200 probands from more than 50 unrelated families harbor missense, nonsense, or splice-site ABCC8 mutations, including recurrent de novo changes and homozygous recessive alleles. A key variant, c.3593C>T (p.Pro1198Leu), has been reported in multiple populations and segregates with disease ([PMID:24843665]). Family studies demonstrate both autosomal dominant and recessive inheritance, with de novo events accounting for many cases.

Functional assays consistently show a gain-of-function mechanism. Patch-clamp studies reveal that ABCC8 mutations reduce ATP inhibition and enhance MgATP activation of KATP channels, stabilizing the open state ([PMID:15962003]). Sulfonylurea drugs act as chemical chaperones in cell models to restore trafficking of misfolded SUR1 and normalize channel gating ([PMID:17575084]).

Clinically, ABCC8 mutation identification guides precision therapy: over 80% of mutation-positive patients can discontinue insulin and achieve normoglycemia on oral sulfonylureas, with fewer hypoglycemic episodes and improved quality of life ([PMID:18662362]). Early molecular diagnosis is therefore critical in all infants with NDM.

Integration of genetic and experimental data supports a definitive gene–disease relationship for ABCC8 and PNDM. While additional rare variants continue to be described, the existing body of work exceeds the ClinGen scoring maximum.

Key take-home: Genetic testing of ABCC8 is essential to initiate targeted sulfonylurea therapy in permanent neonatal diabetes mellitus, transforming lifelong management.

References

• Pediatric diabetes • 2008 • Diagnosis and treatment of neonatal diabetes: a United States experience. PMID:18662362
• Journal of diabetes investigation • 2013 • Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus. PMID:24843665
• The Journal of clinical endocrinology and metabolism • 2007 • Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. PMID:17213273
• EMBO Journal • 2005 • Kir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2-SUR1 interactions. PMID:15962003
• Journal of clinical research in pediatric endocrinology • 2012 • Permanent neonatal diabetes mellitus: same mutation, different glycemic control with sulfonylurea therapy on long-term follow-up. PMID:22672870
• Pediatric diabetes • 2013 • Permanent neonatal diabetes mellitus: prevalence and genetic diagnosis in the SEARCH for Diabetes in Youth Study. PMID:23050777

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