Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia

Abstract

Recessive inactivating mutations in the ABCC8 and KCNJ11 genes encoding the adenosine triphosphate-sensitive potassium (K(ATP)) channel subunit sulphonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel subunit (Kir6.2) are the most common cause of hyperinsulinaemic hypoglycaemia (HH). Most of these patients do not respond to treatment with the (K(ATP)) channel agonist diazoxide. Dominant inactivating ABCC8 and KCNJ11 mutations are less frequent, but are usually associated with a milder form of hypoglycaemia that is responsive to diazoxide therapy. We studied five patients from four families with HH who were unresponsive to diazoxide and required a near total pancreatectomy. Mutations in KCNJ11 and ABCC8 were sought by sequencing and dosage analysis. Three novel heterozygous ABCC8 mis-sense mutations (G1485E, D1506E and M1514K) were identified in four probands. All the mutations affect residues located within the Nucleotide Binding Domain 2 of the SUR1 subunit. Testing of family members showed that the mutations had arisen de novo with dominant inheritance in one pedigree. This study extends the clinical phenotype associated with dominant (K(ATP)) channel mutations to include severe congenital HH requiring near total pancreatectomy in addition to a milder form of diazoxide responsive hypoglycaemia. The identification of dominant vs recessive mutations does not predict clinical course but it is important for estimating the risk of HH in future siblings and offspring.

Fig 1

Microsatellite analysis of markers spanning 15.5 Mb on chromosome 11p15.5-15.1 in family 2 with hyperinsulinaemic hypoglycaemia (HH) resulting from a heterozygous D1506E mutation in the ABCC8 gene. ABCC8 is located between markers D11S1981 and D11S902. Black bars indicate the haplotype co-segregating with hyperinsulinism. Squares denote males, circles females, and black symbols show individuals affected with HH. Genotypes are provided below each symbol and an arrow points to the proband.

Fig 2

(a and b) Comparison of the histology of the resected pancreas from the proband of family 2 and a patient with recessively inherited congenital hyperinsulinism because of ABCC8 mutations. (a) Haematoxylin & eosin (H & E)-stained sections showing the presence of scattered endocrine cells with large and frequently giant endocrine nuclei. The endocrine tissue was poorly organized into islets. (b) H & E-stained sections of pancreatic tissue from a patient with recessive ABCC8 mutations showing the large and frequently giant endocrine nuclei and irregularly sized islets.