Mutation spectra ofABCC8 gene in Spanish patients with hyperinsulinism of infancy (HI)

Abstract

Hyperinsulinism of Infancy (HI) is a clinical disorder characterized by deregulation of insulin secretion that leads to profound hypoglycemia. Mutations in genes encodingthe ATP-regulated potassium channels of the pancreatic β-cell, namely ABCC8 (SUR1) and KCNJ11 (Kir6.2), are the major genetic known cause of the disease. To elucidate the genetic etiology of HI in the uncharacterized Spanish population, we conducted extensive sequencing analysis of the ABCC8 (83.5Kb) and KCNJ11 (1.7Kb) genes in 34 Spanish HI patients. Mutations in ABCC8 were detected for both alleles in 13 patients, while ten patients carried only one mutation in one of the ABCC8 alleles. We have detected 22 novel and seven previously described mutations in ABCC8, ∼60% of them lead to a premature termination signal, which would result in truncated SUR1 proteins. No mutations were found in the KCNJ11 gene. In addition, we report for the first time a 3914bp macrodeletion associated with the HI disorder. The potential pathogenicity of several additional variants is discussed. The spatial pattern of three pathological mutations suggests possible geographical founder effects. This work reveals for first time the involvement of KATP channels in the pathogenesis of an important proportion (∼68%) of Spanish HI patients. The spectrum of mutations in Spanish HI patients provides an important tool for diagnosis and prognosis of HI patients in the Spanish population, as well as for genetic counseling of HI families. © 2006 Wiley-Liss, Inc.KEY WORDS: hyperinsulinism; ABCC8; KCNJ11; mutation spectra; Spanish INTRODUCTIONATP-sensitive potassium channels (KATP) are major regulators of glucose-induced insulin secretion in pancreatic ß cells . Mutations in ABCC8 (MIM# 600509) and KCNJ11 (MIM# 600937) genes have been shown to result in defects in the KATP channel function leading to Hyperinsulinism of Infancy HI, a disease characterized by deregulated insulin secretion that leads to severe and recurrent hypoglycaemias DOI: 10.1002/humu.9401 2 Fernández-Marmiesse et al. ; references therein). Estimates for the incidence of this disorder vary from 1/40.000 live births in Northern Europe (Bruining et al. 1990) to 1/2675 live births in Saudi Arabia (Mathew et al. 1988). The severity of the disease varies from a mild form, which responds to medical treatment, to severe drug-resistant form, which may need resection of the pancreas. Early diagnosis is important to avoid irreversible brain damage due to profound hypoglycaemia. Clinical manifestations of HI, which occurs predominantly in neonates and infants, include large birth weight for gestational age, seizures, cyanosis and coma (Hussain et al. 2000).Although both autosomal dominant and recessive inheritance of HI have been described, this disorder is inherited as an autosomal recessive trait in the majority of familial cases. Most of HI cases (>95%) are sporadic, and two histopathologic lesions can be distinguished, a diffuse and a focal form, each with a prevalence of ∼50% . It has been demonstrated that focal ca...

Clinical and genetic characterization of congenital hyperinsulinism in Spain

“…In our study, a genetic diagnosis was obtained in 56% of patients with CHI tested, similar to figures reported in other studies (4,16,17,18), although slightly lower than that found in the only previous study in a Spanish population (19). ABCC8 inactivating mutations are the leading genetic cause of CHI in our patients.…”

“…An exception within this group is the patient with compound heterozygous mutation in ABCC8 (patient 5) who did respond to diazoxide treatment. This patient had a p.Ala578_Leu582dup mutation in the paternal allele, a mutation that has been described to be associated with different situations in two patients with the mutation in heterozygosis and paternally inherited, who had a severe phenotype and did not respond to diazoxide treatment (5,20), and in one patient with a compound heterozygous mutation, who was managed with continuous feeding (19). In the maternal allele, our patient has a novel missense mutation p.Ala1575Pro, and in silico analysis showed discrepant results (Table 3).…”

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

“…Diffuse CHI has been described in the literature with paternally inherited ABCC8/KCNJ11 mutations. Fernandez-Marmiesse et al (10) reported five patients with paternally inherited K ATP mutations and whose post pancreatectomy pathology result was not consistent with that of focal lesion. Similar findings have been reported by other studies (1,21,27,30).…”

“…Mutations in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, subunits: Kir6.2 encoded by KCNJ11 and SUR1 encoded by ABCC8 gene (2). Both genes are localised in the 11p15.1 region and mutations in these accounts for the majority of CHI patients (3,4,5,6,7,8,9,10,11).…”

“…Furthermore, diffuse disease can either be diazoxide-responsive or unresponsive depending on the underlying molecular basis of the mutation and other unclear genetic or environmental influences (28). There are isolated case reports of heterozygous paternally inherited ABCC8/ KCNJ11 mutations leading to diffuse CHI in the literature (3,10,29,30). The proportion of patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations who develop focal CHI has not been reported in any study so far.…”