Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism - Association with a reduction to hamozygosity of a mutation in ABCC8 or KCNJ11

Congenital hyperinsulinism (CHI), previously named persistent hyperinsuline mic hypoglycemia of infancy, is characterized by profound hypoglycemia beca use of excessive insulin secretion. CHI presents as two different morpholog ical forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasi a, which can be cured by partial pancreatectomy. Recently, we have shown th at focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allel e of the gene encoding the regulating subunit of the K-ATP(+) channel, the sulfonylurea receptor (ABCC8 or SUR1), In the present study on a large seri es of 31 patients, describing both morphological features and molecular dat a, we report that 61% of cases (19 out of 31) tarried a paternally inherite d mutation not only in the ABCC8 gene as previously described but also in t he second gene encoding the K-ATP(+) channel, the inward rectifying potassi um channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreo ver our results are consistent with the presence of a duplicated paternal 1 1p15 allele probably because of mitotic recombination of reduplication of t he paternal chromosome after somatic loss of the maternal chromosome. In ag reement with the loss of the maternal chromosome, the level of expression o f a maternally expressed tumor suppressor gene, H19, was greatly reduced co m pared to the level of expression of the paternally expressed growth promo ter gene, IGF2, The expression of IGF2 was on average only moderately incre ased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in t he 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KC NJ11-recessive mutation, The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secre tion of insulin.