Molecular and Clinical Analysis of Japanese Patients with Persistent Congenital Hyperinsulinism: Predominance of Paternally Inherited Monoallelic Mutations in the K<sub>ATP</sub>Channel Genes

Yorifuji, Tohru; Kawakita, Rie; Nagai, Shizuyo; Sugimine, Akinori; Doi, Hiraku; Nomura, Anryu; Masue, Michiya; Nishibori, Hironori; Yoshizawa, Akihiko; Okamoto, Shinya; Doi, Ryuichiro; Üemoto, Shinji; Nagasaka, Hironori

doi:10.1210/jc.2010-1281

Cited by 40 publications

(53 citation statements)

References 17 publications

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“…The other interesting observation in our study was the low prevalence of monoallelic K ATP mutation (2/35; 5.7%). This is in sharp contrast to observations from genetic analysis of patients from Korea and Japan, where the single mutation rate was between 50 and 60% (Table 4) (20,23). In the study by Kapoor et al, monoallelic K ATP mutation was present in 14.6% of patients, whereas 48% of patients had monoallelic K ATP mutation in the study by Snider et al (21,22).…”

Section: Discussioncontrasting

confidence: 56%

Clinical characteristics and phenotype–genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations

Demirbilek

Arya

Özbek

et al. 2014

European Journal of Endocrinology

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Objective: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients. Design and methods: A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected. Results: Diazoxide unresponsiveness was observed in nearly half of the patients (nZ17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (nZ18), mutations were identified in two patients (11%). Genotype-phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P!0.0001). Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydraterich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients. Conclusions: This is the largest study to report genotype-phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.

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Section: Discussioncontrasting

confidence: 56%

Clinical characteristics and phenotype–genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations

Demirbilek

Arya

Özbek

et al. 2014

European Journal of Endocrinology

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“…These results are substantially higher than those of 0-8% (30,32,(36)(37)(38) of KCNJ11 mutations resulting in K ATP channel variation found in studies that analyzed all mutations of the ABCC8 and KCNJ11 genes.…”

Section: Discussionmentioning

confidence: 56%

“…Of these patients, 50% (5/10) inherited the mutation from their father. Previous studies reported that the single mutation rate was 40-43% in Western countries (37,39) and 89.5% in Japan (38) and that the paternal inheritance rate was 70 and 84.2% respectively. Our data revealed a high proportion of single mutations with a lower paternal inheritance rate.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, 80% of patients who underwent surgery in a Japanese study (38) exhibited focal disease and all had a single paternally inherited mutation. Compound heterozygous mutations were found in 33% (2/6) of patients with diffuse CHI, heterozygous mutations were found in 50% (3/6) of these patients, of which the only diazoxide-responsive patient had a paternally inherited mutation, and no mutations were identified in 17% (1/6) of these patients in our study cohort.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

Park

Flanagan

Hussain

et al. 2011

European Journal of Endocrinology

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Objective: Congenital hyperinsulinism (CHI) is characterized by persistent hypoglycemia due to the inappropriate insulin secretion. Inactivating mutations in the ABCC8 and KCNJ11 genes, which encode the sulfonylurea receptor 1 and Kir6.2 subunits of the ATP-sensitive K C (K ATP ) channel in pancreatic b-cell, are the most common cause of CHI. We studied the genetic etiology and phenotypes of CHI in Korean patients. Methods: ABCC8 and KCNJ11 mutational analysis was performed in 17 patients with CHI. Medical records were retrospectively reviewed to identify phenotypes. Results: Mutations (12 ABCC8 and three KCNJ11) were identified in 82% (14/17) of patients. Of these, nine ABCC8 mutations (E100X, W430X, c.1630C1GOC, D813N, Q923X, E1087_A1094de-linsDKSDT, Q1134H, H1135W, and E1209Rfs) and one KCNJ11 mutation (W91X) were novel. Of the 14 patients, four had confirming recessively inherited CHI. The remaining ten patients had single heterozygous mutations. The majority (12/17) of patients were medically responsive. Of the five diazoxide-responsive patients, four had an ABCC8 mutation. The five patients unresponsive to medical management and one diazoxide-responsive patient underwent pancreatectomy and had diffuse histology. Of the operated six patients, two had recessively inherited mutations; three patients had a single heterozygous mutation (one maternally and two paternally inherited); and one patient had no identifiable K ATP channel mutation. Conclusions: This is the first study to report genotype and phenotype correlations among Korean patients with CHI. Mutations in ABCC8 and KCNJ11 are the most common causes of CHI in Korean patients. Similar to other studies, there is marked genetic heterogeneity and no clear genotypephenotype correlation.European Journal of Endocrinology 164 919-926

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“…Further clinical evaluation was not possible as the child unfortunately developed bronchopneumonia/sepsis and subsequently disseminated intravascular coagulation (DIVC) during subsequent hospitalization and died. Previous studies showed that the K ATP channel activity was seen to be decreased (Tornovsky et al, 2004;Yorifuji et al, 2011) in individuals with Gly111Arg mutant SUR1 protein. This was also demonstrated in electrophysiological studies of cultured islets which revealed defects in the electrical activity of K ATP channels (De Vroede et al, 2004).…”

Section: Discussionmentioning

confidence: 92%

NovelABCC8(SUR1) Gene Mutations in Asian Indian Children with Congenital Hyperinsulinemic Hypoglycemia

Joghee

Varadarajan

Kanthimathi

et al. 2014

Annals of Human Genetics

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SummaryCongenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the β-cell ATP-sensitive K + channel (K ATP channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K ATP mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444* , Leu724Pro, Ala847Thr, Trp898 * , IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598 * ) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling.

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Molecular and Clinical Analysis of Japanese Patients with Persistent Congenital Hyperinsulinism: Predominance of Paternally Inherited Monoallelic Mutations in the K_ATPChannel Genes

Abstract: The majority of the Japanese patients with K(ATP) channel hyperinsulinism (84.2%) demonstrated paternally inherited monoallelic mutations that accurately predicted the presence of the focal form.

Cited by 40 publications

References 17 publications

Clinical characteristics and phenotype–genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations

Clinical characteristics and phenotype–genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

NovelABCC8(SUR1) Gene Mutations in Asian Indian Children with Congenital Hyperinsulinemic Hypoglycemia

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Molecular and Clinical Analysis of Japanese Patients with Persistent Congenital Hyperinsulinism: Predominance of Paternally Inherited Monoallelic Mutations in the KATPChannel Genes

Abstract: The majority of the Japanese patients with K(ATP) channel hyperinsulinism (84.2%) demonstrated paternally inherited monoallelic mutations that accurately predicted the presence of the focal form.

Cited by 40 publications

References 17 publications

Clinical characteristics and phenotype–genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations

Clinical characteristics and phenotype–genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

NovelABCC8(SUR1) Gene Mutations in Asian Indian Children with Congenital Hyperinsulinemic Hypoglycemia

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Molecular and Clinical Analysis of Japanese Patients with Persistent Congenital Hyperinsulinism: Predominance of Paternally Inherited Monoallelic Mutations in the K_ATPChannel Genes