Permanent Neonatal Diabetes Caused by Dominant, Recessive, or Compound Heterozygous SUR1 Mutations with Opposite Functional Effects

Abstract

Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.

Insulin gene mutations as a cause of permanent neonatal diabetes

“…In the large Exeter permanent ND series they accounted for 38% of cases in which the genetic etiology was unknown. This finding is Ϸ20% of all permanent ND cases, similar to ABCC8 mutations (19%), but less than KCNJ11 mutations (30%) (18). KCNJ11 and ABCC8 mutations also cause transient ND for which the major cause is abnormalities of imprinting of the ZAC region on chromosome 6q (19).…”

“…These patients were selected from the International Society for Pediatric and Adolescent Diabetes collection at the Peninsula Medical School on the basis of normal sequencing of the coding region of the KCNJ11 and ABCC8 genes, and the availability of parental DNA. They were used in a previous study of ABCC8 in permanent ND (18). The clinical and biochemical characteristics of these patients were obtained by the patients' local endocrinologists or during a physical examination.…”

Heterozygous ABCC8 mutations are a cause of MODY

“…The R1380H mutation (probands 1 and 2) has been reported previously in patients with TNDM [3,8]. V1523L (proband 5) was previously identified in a patient with PNDM who was a compound heterozygote for V1523L and T229I [5]. The Q485R mutation arose de novo in proband 6 and is novel, although a different mutation at this residue, Q485H, has been reported in a patient with PNDM [10].…”

“…The single exon of the KCNJ11 gene and the 39 exons of the ABCC8 gene were amplified and sequenced as previously described [5]. Sequences were compared with the published sequences, NM_000525.3 and NM_000352.2, which incorporates the alternatively spliced residue in exon 17 (L78224).…”

“…This may be permanent neonatal diabetes (PNDM) or transient neonatal diabetes (TNDM) [2][3][4][5]. TNDM remits but often relapses in later life [3,4].…”