David E. Barton
National Centre for Medical Genetics; Our Lady's Hospital for Sick Children
Persistent neonatal hyperinsulinemic hypoglycemia (HI) is a clinically and genetically heterogeneous disorder characterized by profound hypoglycemia due to inappropriate secretion of insulin. At the molecular level, mutations in the sulfonylurea receptor (SUR-1) and the potassium channel subunit (KIR6.2) on chromosome 11p have been identified in autosomal recessive forms of the disease, and mutations in the glutamate dehydrogenase and glucokinase genes in autosomal. dominant forms. We present the results of molecular analysis of 3 HI patients with focal ß-cell hyperplasia, paternally inherited germline SUR-1 mutations (1630+1 G to T, A1493T and 3992-9 G to A, respectively) and somatic loss of the maternal chromosome 11 p. We propose a model where the focal ß-cell hyperplasia. is a result of somatic loss of the maternal 11p (containing the imprinted p57KIP2 and H19 tumor suppressor genes and the non-imprinted SUR-1 and KIR6.2 genes). The additional presence of a paternally derived SUR-1 mutation results in a reduction to homozygosity for the SUR-1 mutation in focal cells, dysregulation of insulin secretion and ultimately to the hyperinsulinism phenotype. Analysis of a further 170 HI probands yielded 37 with two SUR-1 mutations and 30 with one SUR-1 mutation. Of those with 1 mutation, parental origin could be determined in 28 and of these 26 were paternally derived (p<0.0008). We propose that allele specific germline mutation of a non-imprinted gene plus somatic deletion of physically adjacent imprinted genes, is a novel mechanism by which a recessive mutation can be expressed in a heterozygous individual.