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

Aim: Mutations in the ABCC8 gene encoding the SUR1 subunit of the pancreatic ATP-sensitive potassium channel cause permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). We reviewed the existing literature, extended the number of cases and explored genotype-phenotype correlations. Methods: Mutations were identified by sequencing in patients diagnosed with diabetes before 6 months without a KCNJ11 mutation. Results: We identified ABCC8 mutations in an additional nine probands (including five novel mutations L135P, R306H, R1314H, L438F and M1290V), bringing the total of reported families to 48. Both dominant and recessive mutations were observed with recessive inheritance more common in PNDM than TNDM (9 vs. 1; p < 0.01). The remainder of the PNDM probands (n = 12) had de novo mutations. Seventeen of twenty-five children with TNDM inherited their heterozygous mutation from a parent. Nine of these parents had permanent diabetes (median age at diagnosis: 27.5 years, range: 13-35 years). Recurrent mutations of residues R1183 and R1380 were found only in TNDM probands and dominant mutations causing PNDM clustered within exons 2-5. Conclusions: ABCC8 mutations cause PNDM, TNDM or permanent diabetes diagnosed outside the neonatal period. There is some evidence that the location of the mutation is correlated with the clinical phenotype.