Congenital hyperinsulinism: Molecular basis of a heterogeneous disease

Clinical and genetic heterogeneity in congenital hyperinsulinism

“…In contrast, somatic events such as loss of heterozygosity might be limited to speci®c focal areas in the pancreas. At present, four genes with three dierent mechanisms are known to cause CHI (Table2) [39,77]. However, mutations in these genes have been found in only 30%±50%, at maximum, of aected patients [38].…”

The molecular basis of persistent hyperinsulinemic hypoglycemia of infancy and its pathologic substrates

“…The disease has been localized to the chromosome locus 11p15.1, which contains the genes for the two subunits, SUR1 ("sulfonylurea receptor") and Kir6.2 ("inward rectifying potassium channel") of the ATP-dependent potassium channel of the beta cell membrane, which has an essential function in the process of insulin secretion [1]. So far 28 different mutations of the sulfonylurea receptor (SUR1) and two mutations of the Kir6.2 gene have been reported [23]. They lead to a loss of function by causing a blockage of the outward K + transport through the potassium channel, which is then followed by permanent depolarization of the beta cell membrane and an increased influx of calcium, resulting in inappropriate insulin release.…”

“…Recently, molecular studies have revealed that PHHI results from at least three basic genetic defects: first, loss-of-function mutations on chromosome locus 11p15.1 affecting the genes of the two subunits SUR1 and KIR6.2 [11,24,34], which form the ATP-dependent potassium channel that is an integral part of the stimulus-secretion coupling apparatus of insulin release; second, gain-of function mutations of genes for enzymes (glucokinase, glutamate dehydrogenase) that regulate the rate of insulin secretion; and third, a two-hit loss-of-heterozygosity (LOH) mechanism in a group of beta cells [9,10], with a specific loss of maternal alleles of the imprinted chromosome region 11p15.1 unmasking a paternally inherited recessive SUR1 or KIR6.2 mutation (for further review cf. [23]). This review will attempt to correlate the different genotypes with the spectrum of pathological changes in PHHI patients described in the literature and found in our own series of 38 patients (see Table 1).…”

Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome

“…Several 'loss-of-function' mutations in the genes for two subunits of an ATP-dependent potassium channel of β cells, SUR1 and K ir 6.2, as well as a single activating mutation of the glucokinase gene, GCK, have been reported (for review see Meissner et al 1999). Furthermore, mutations of the glutamate dehydrogenase (GlDH, EC 1.4.1.3) gene, GLUD1, have been shown to be responsible for a distinct type of congenital hyperinsulinism (Stanley et al 1998) which is clinically characterized by the concomitant occurrence of hyperammonemia and (in familial cases) the characteristics of autosomal dominant inheritance (Zammarchi et al 1996;Weinzimer et al 1997).…”