ABCC8 – Maturity-Onset Diabetes of the Young (MODY12)

ABCC8 encodes the sulfonylurea receptor 1 (SUR1), a regulatory subunit of the pancreatic β-cell KATP channel. Pathogenic heterozygous variants in ABCC8 cause autosomal dominant maturity-onset diabetes of the young (MODY12), characterized by persistent mild hyperglycemia, non-ketotic presentation, and variable age of onset (<25 y) ([PMID:21214702]). Patients often retain endogenous insulin secretion and may exhibit complications such as retinopathy and microalbuminuria when untreated ([PMID:27538677]).

MODY12 follows an autosomal dominant inheritance pattern with evidence of segregation in multiple pedigrees. For example, the ABCC8 c.250G>A (p.Val84Ile) variant co-segregated with mild hyperglycemia in five additional family members across three generations ([PMID:21214702]). Similar familial transmission and disease clustering have been reported in over 40 unrelated probands and multi-generation kindreds ([PMID:36626423], [PMID:37071846]).

The ABCC8 variant spectrum in MODY12 includes >80 missense changes, several splice-site and frameshift alleles (e.g., c.4609dup (p.His1537ProfsTer22)), and rare deep-intronic alterations. Recurrent mutations are reported but no clear founder haplotype has been established. Representative variant: c.250G>A (p.Val84Ile) ([PMID:21214702]).

Functional studies reveal that MODY-causing ABCC8 mutations disrupt KATP channel trafficking and gating. Many TMD0-domain mutants (e.g., p.Phe128Lys) exhibit endoplasmic reticulum retention rescued by sulfonylurea chaperones, whereas others alter ATP/ADP sensitivity via defective NBF interfaces ([PMID:10993895], [PMID:17584766]). These concordant in vitro findings support a loss-of-function mechanism underlying β-cell dysfunction.

No substantial conflicting reports have emerged; all studied ABCC8 variants demonstrate functional impairment concordant with the AD MODY12 phenotype. Variable expressivity and age-dependent penetrance account for mild hyperglycemia in some carriers.

Integration of genetic and experimental data establishes a definitive ABCC8–MODY12 association. Clinical genetic testing should include ABCC8 for patients with nondistinctive mild hyperglycemia and family history. Early molecular diagnosis enables precision treatment—sulfonylureas, GLP-1 receptor agonists, or SGLT2 inhibitors—improving glycemic control and reducing hypoglycemia risk.

Key Take-home: Heterozygous ABCC8 variants cause definitive AD MODY12 via KATP channel dysfunction, guiding targeted genetic testing and tailored therapy.

References

• Pediatric Diabetes • 2011 • Familial mild hyperglycemia associated with a novel ABCC8-V84I mutation within three generations. PMID:21214702
• Diabetes Therapy • 2016 • ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): Clinical Features and Treatment Perspective. PMID:27538677
• Medicine • 2022 • A case report of maturity-onset diabetes of the young (MODY12) in a Chinese Han patient with a novel ABCC8 gene mutation. PMID:36626423
• J Pediatr Endocrinol Metab • 2023 • ABCC8-related maturity-onset diabetes of the young: switching from insulin to sulphonylurea therapy: how long do we need for a good metabolic control? PMID:37071846
• J Biol Chem • 2001 • Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy. PMID:10993895
• Hum Mol Genet • 2007 • Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. PMID:17584766

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