Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations

Abstract

Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive K + (K ATP ) channel in the pancreatic β cell. Though most disease-causing mutations of the 2 genes encoding K ATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating K ATP mutations, we have identified and characterized 16 families with 14 different dominantly inherited K ATP mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a K ATP channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant K ATP hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited K ATP mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant K ATP hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy.

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

“…Although there was no history of hypoglycaemia in the fathers of our cohort, formal evaluation with controlled provocation fasting studies has not been done. Other studies also have reported parents to be asymptomatic carriers of dominant acting mutations (41). In view of severe diazoxide side effects and parental request, three patients from this subgroup underwent 18 F DOPA-PET CT imaging to avoid long-term treatment with diazoxide.…”

A Neonatal Case of Congenital Hyperinsulinism Due to Homozygous KCNJ11 Gene Mutation

“…KH, genellikle otozomal resesif geçiş göstermek-le beraber otozomal dominant kalıtılan formları da tanımlanmıştır (8) . Olguların çoğunun SUR1 (ABCC8) genindeki mutasyonlardan kaynaklandığı bildirilmiş ve bugüne kadar 150'den fazla mutasyon tespit edilmiştir (9,10) .…”

Nieinsulinowa hipoglikemia trzustkowa u dorosłych — przegląd genetyki

“…In case of the diffused • severe form of neonatal hypoglycaemia [48,49] • diffuse FHI** [6] -dominant:…”

“…• milder form [48,49] • focal FHI -caused by a paternal mutation of one of the genes and a specific loss of maternal alleles [8] Dominant, activating [10,[14][15][16] Dominant, activating [4,19] Relatively mild FHI, may escape recognition in infancy [20] Recessive, loss of function [4,[25][26][27][28] Dominant, increased expression [29] Dominant, loss of function [35] Also associated with MODY1 (HNF4a) and MODY3 (HNF1a) [35] Dominant, loss of function Characteristic Large birth weight [4] Increased risk of diabetes in adulthood [4] Normal birth weight [15] Hyperammonaemia [21] Leucine-dependent protein-stimulated hypoglycaemia [4] Elevated urinary 3-hydroxyglutaric acid excretion [4] Leucine-dependent protein-stimulated hypoglycaemia [25] hypoglycaemia after intensive exercise [29] Large birth weight [34] *Cases with dominant KATP mutations may be responsive to diazoxide [48,49]. **Most cases.…”