Heterozygous ABCC8 mutations are a cause of MODY

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of ATP-sensitive potassium channels.
• Activating ABCC8 mutations cause neonatal diabetes, while inactivating mutations cause congenital hyperinsulinism.
• Sulfonylurea sensitivity is characteristic of HNF1A and HNF4A MODY, but not all such patients have mutations in these genes.

Purpose of the Study:

• To investigate if ABCC8 gene mutations cause Maturity Onset Diabetes of the Young (MODY) responsive to sulfonylurea therapy.
• To identify novel mutations in ABCC8 associated with MODY phenotypes.

Main Methods:

• Sequencing of the ABCC8 gene in 85 patients with suspected MODY, negative for HNF1A/4A mutations, and sensitive to sulfonylureas.
• Analysis of mutation types (previously reported and novel) and their clinical correlation.

Main Results:

• ABCC8 mutations were identified in 8% (7/85) of probands.
• Four novel mutations (E100K, G214R, Q485R, N1245D) were discovered.
• Four probands met MODY criteria, including late-onset cases and a de novo mutation.

Conclusions:

• ABCC8 mutations can present as MODY with clinical features overlapping HNF1A/4A MODY.
• ABCC8 gene sequencing should be considered in the diagnostic workup of suspected HNF1A/4A MODY to ensure optimal patient management.