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Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia.

ABSTRACT: Congenital hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a glucose metabolism disorder characterized by unregulated secretion of insulin and profound hypoglycemia. From a morphological standpoint, there are two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in approximately 30% of operated sporadic cases, and a diffuse form. In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were observed. Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome (BWS), also associated with neonatal but transient hyperinsulinism. However, this region also contains the sulfonylurea receptor (SUR1) gene and the inward rectifying potassium channel subunit (KIR6.2) gene, involved in recessive familial forms of PHHI, but not known to be imprinted. Although the parental bias in loss of maternal alleles did not argue in favor of their direct involvement, the LOH may also unmask a recessive mutation leading to persistent hyperinsulinism. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation in four patients with a focal form of PHHI. Thus, this somatic event which leads both to beta cell proliferation and to hyperinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder.

SUBMITTER: Verkarre V

PROVIDER: S-EPMC508975 | biostudies-other | 1998 Oct

REPOSITORIES: biostudies-other

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Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia.

Verkarre V V Fournet J C JC de Lonlay P P Gross-Morand M S MS Devillers M M Rahier J J Brunelle F F Robert J J JJ Nihoul-Fékété C C Saudubray J M JM Junien C C

The Journal of clinical investigation 19981001 7

Congenital hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a glucose metabolism disorder characterized by unregulated secretion of insulin and profound hypoglycemia. From a morphological standpoint, there are two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in approximately 30% of operated sporadic cases, and a diffuse form. In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted ...[more]

PMID: 9769320

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Project description:Congenital hyperinsulinism (CHI), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia because of excessive insulin secretion. CHI presents as two different morphological forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasia, which can be cured by partial pancreatectomy. Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele 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 series of 31 patients, describing both morphological features and molecular data, we report that 61% of cases (19 out of 31) carried a paternally inherited mutation not only in the ABCC8 gene as previously described but also in the second gene encoding the K(+)(ATP) channel, the inward rectifying potassium channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreover our results are consistent with the presence of a duplicated paternal 11p15 allele probably because of mitotic recombination or reduplication of the paternal chromosome after somatic loss of the maternal chromosome. In agreement with the loss of the maternal chromosome, the level of expression of a maternally expressed tumor suppressor gene, H19, was greatly reduced compared to the level of expression of the paternally expressed growth promoter gene, IGF2. The expression of IGF2 was on average only moderately increased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in the 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KCNJ11-recessive mutation. The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secretion of insulin.

Dataset Information

Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia.

Publications

Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia.

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