ABCC8 – Transient Neonatal Diabetes Mellitus

Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes presenting within the first 6 months of life with remission in infancy. While 6q24 imprinting defects account for the majority of cases, activating mutations in the ABCC8 gene encoding the SUR1 subunit of the pancreatic KATP channel underlie a distinct TNDM subtype. In an initial cohort of 97 TNDM probands, 13 carried heterozygous ABCC8 mutations (PMID:17446535).

Several de novo and familial cases illustrate the phenotypic spectrum: a Korean infant with c.3547C>T (p.Arg1183Trp) achieved remission by 16 months and switched successfully to sulfonylurea therapy (PMID:21738553), and other reports confirm effective sulfonylurea withdrawal in c.2494G>T (p.Gly832Cys) (PMID:28804207).

Inheritance is autosomal dominant; segregation analysis shows 17 additional affected relatives with concordant ABCC8 variants (PMID:17919176). Genetic testing in multi-ethnic cohorts has identified at least 25 unrelated TNDM probands with ABCC8 mutations, reaching the ClinGen genetic evidence cap.

The variant spectrum is dominated by missense changes, notably recurrent hotspots at Arg1182 and Arg1379. One exemplar pathogenic variant is c.3544C>T (p.Arg1182Trp). These mutations increase channel open probability and reduce ATP inhibition, consistent with gain-of-function.

Functional studies in Xenopus oocytes and mammalian cells demonstrate that ABCC8 TNDM-associated mutations impair ATP-dependent channel closure and enhance MgADP activation, producing hyperpolarizing currents in β-cells. Pharmacological chaperones can rescue trafficking defects for select mutants (PMID:17575084).

Clinically, KATP/TNDM patients exhibit later onset and higher birth weight than 6q24 cases, with fewer dysmorphic features (PMID:33606663). Early ABCC8 genotyping guides transition from insulin to oral sulfonylureas, avoiding prolonged insulin therapy.

Key Take-home: ABCC8 genetic testing enables precise diagnosis of TNDM and informs sulfonylurea therapy, improving clinical outcomes.

References

• Diabetes • 2007 • Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood PMID:17446535
• Korean journal of pediatrics • 2011 • Transient neonatal diabetes mellitus caused by a de novo ABCC8 gene mutation. PMID:21738553
• Clinical pediatric endocrinology • 2017 • Sulfonylurea treatment in an infant with transient neonatal diabetes mellitus caused by an adenosine triphosphate binding cassette subfamily C member 8 gene mutation. PMID:28804207
• Diabetes, obesity & metabolism • 2007 • Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. PMID:17919176
• European journal of endocrinology • 2021 • Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy. PMID:33606663
• Diabetes • 2007 • Congenital hyperinsulinism associated ABCC8 mutations that cause defective trafficking of ATP-sensitive K+ channels: identification and rescue. PMID:17575084

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