New <i>ABCC8</i> Mutations in Relapsing Neonatal Diabetes and Clinical Features

Vaxillaire, Martine; Dechaume, Aurélie; Busiah, Kanetee; Cavé, Hélène; Pereira, Sabrina Bernárdez; Scharfmann, Raphaël; Nanclares, Guiomar Perez de; Castaño, Luís; Froguel, Philippe; Polak, Michel

doi:10.2337/db06-1540

Cited by 82 publications

(47 citation statements)

References 24 publications

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“…Successful transfer from insulin to oral sulfonylureas has been described in eight patients with neonatal diabetes due to SUR1 mutations (9,10,(15)(16)(17). This study will examine the treatment response to sulfonylureas in a cohort of 27 patients with diabetes due to SUR1 mutations to identify whether they can be used effectively and how their transfer and treatment differ from that in Kir6.2 patients.…”

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Effective Treatment With Oral Sulfonylureas in Patients With Diabetes Due to Sulfonylurea Receptor 1 (SUR1) Mutations

et al. 2008

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OBJECTIVE -Neonatal diabetes can result from mutations in the Kir6.2 or sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K ϩ channel. Transfer from insulin to oral sulfonylureas in patients with neonatal diabetes due to Kir6.2 mutations is well described, but less is known about changing therapy in patients with SUR1 mutations. We aimed to describe the response to sulfonylurea therapy in patients with SUR1 mutations and to compare it with Kir6.2 mutations.RESEARCH DESIGN AND METHODS -We followed 27 patients with SUR1 mutations for at least 2 months after attempted transfer to sulfonylureas. Information was collected on clinical features, treatment before and after transfer, and the transfer protocol used. We compared successful and unsuccessful transfer patients, glycemic control before and after transfer, and treatment requirements in patients with SUR1 and Kir6.2 mutations. RESULTS -Twenty-three patients (85%) successfully transferred onto sulfonylureas without significant side effects or increased hypoglycemia and did not need insulin injections. In these patients, median A1C fell from 7.2% (interquartile range 6.6 -8.2%) on insulin to 5.5% (5.3-6.2%) on sulfonylureas (P ϭ 0.01). When compared with Kir6.2 patients, SUR1 patients needed lower doses of both insulin before transfer (0.4 vs. 0.7 units ⅐ kg Ϫ1 ⅐ day Ϫ1 ; P ϭ 0.002) and sulfonylureas after transfer (0.26 vs. 0.45 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; P ϭ 0.005).CONCLUSIONS -Oral sulfonylurea therapy is safe and effective in the short term in most patients with diabetes due to SUR1 mutations and may successfully replace treatment with insulin injections. A different treatment protocol needs to be developed for this group because they require lower doses of sulfonylureas than required by Kir6.2 patients.

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Effective Treatment With Oral Sulfonylureas in Patients With Diabetes Due to Sulfonylurea Receptor 1 (SUR1) Mutations

et al. 2008

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“…These phenotype specificities depend on the mutation in Kir6.2 or SUR1: from mild transient hyperglycemia to PND for SUR1 mutations (4,8,9) and from PND to more severe phenotypes associated with developmental delay and epilepsy usually for Kir6.2 and for some SUR1 mutations (10,11). In the patients referred to the French ND Study Group, over 50 cases presenting with very-early-onset diabetes are not yet defined for their molecular origin (8). This suggests that other gene defects are involved in key mechanisms regulating insulin processing and secretion and/or the survival process of insulin-producing ␤-cells.…”

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confidence: 99%

“…The H family (Table 1) was referred to us to sequence ABCC8, as mutations in this gene may be present in patients with diabetes from the neonatal period to young adulthood (4,8). As GCK (MODY2) and HNF1A (MODY3) sequences were also found to be normal in this family, the proband HA was included in the current study, despite diabetes appearing like nonautoimmune early-onset type 1 rather than bona fide neonatal diabetes.…”

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“…In the present study, 38 PND patients from the French ND cohort and 1 child with nonautoimmune early-infancy diabetes, who are negative for a mutation in GCK, KCNJ11, and ABCC8 (4,8,10), were screened for the INS gene by direct sequencing. The H family (Table 1) was referred to us to sequence ABCC8, as mutations in this gene may be present in patients with diabetes from the neonatal period to young adulthood (4,8).…”

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Heterozygous Missense Mutations in the Insulin Gene Are Linked to Permanent Diabetes Appearing in the Neonatal Period or in Early Infancy

et al. 2008

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OBJECTIVE—Permanent neonatal diabetes (PND) is defined by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life. Several genes, including KCNJ11 and ABCC8, which encode the two subunits of the ATP-sensitive K+ channel (KATP channel) can cause PND. Mutations in the insulin (INS) gene have been recently described in families with neonatal diabetes. Our study aimed to investigate the genetic anomalies and clinical heterogeneity in PND patients who are negative for a KATP channel mutation. RESEARCH DESIGN AND METHODS—We screened the INS gene by direct sequencing in 38 PND patients and in one child with nonautoimmune early-infancy diabetes, where no mutation in GCK, KCNJ11, and ABCC8 was identified. A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found with an INS mutation. RESULTS—We identified three missense mutations in the INS gene in four probands. Two of four mutations were inherited in a dominant manner, and the familial description evidenced a marked variability in age of diagnosis and disease progression. In our cohort, the INS mutations may represent ∼10% of all permanent neonatal diabetes cases, having a later presentation of diabetes and no associated symptoms compared with cases with KATP channel mutations. CONCLUSIONS—Heterozygous INS gene mutations can cause isolated permanent early-infancy diabetes and should be assessed in neonatal as well as in childhood diabetes appearing like type 1, when autoimmune markers are absent. New pharmacogenomic strategies may be applicable, since residual β-cell function is still present in some patients.

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“…Etiologies other than autoimmunity are far more prevalent if diabetes is diagnosed before the age of 6 months (2). Recent developments have highlighted the importance of ion channel mutations ("channelopathies") in the etiology of both permanent and transient forms of this condition (3)(4)(5). The pancreatic ␤-cell ATP-sensitive K ϩ channel (K ATP channel) is composed of four inward rectifying K ϩ channel (Kir6.2) subunits, encoded by the gene KCNJ11, and four sulfonylurea receptor (SUR1) subunits encoded by ABCC8.…”

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Mosaic Paternal Uniparental Isodisomy and an ABCC8 Gene Mutation in a Patient With Permanent Neonatal Diabetes and Hemihypertrophy

et al. 2008

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OBJECTIVE-Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the pancreatic ATP-sensitive K ϩ channel are the most common cause of permanent neonatal diabetes. In contrast to KCNJ11, where only dominant heterozygous mutations have been identified, recessively acting ABCC8 mutations have recently been found in some patients with neonatal diabetes. These genes are co-located on chromosome 11p15.1, centromeric to the imprinted BeckwithWiedemann syndrome (BWS) locus at 11p15.5. We investigated a male with hemihypertrophy, a condition classically associated with neonatal hyperinsulinemia and hypoglycemia, who developed neonatal diabetes at age 5 weeks. RESEARCH DESIGN AND METHODS-The KCNJ11 andABCC8 genes and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and his parents. RESULTS-A paternally inherited activating mutation (N72S) inthe ABCC8 gene was identified in the proband. The mutation was present at 70% in the patient's leukocytes and 50% in buccal cells. Microsatellite analysis demonstrated mosaic segmental paternal uniparental isodisomy (UPD) of 11pter-11p14 in the proband that encompassed the ABCC8 gene and the BWS locus.CONCLUSIONS-We report a patient with neonatal diabetes, hemihypertrophy, and relatively high birth weight resulting from telomeric segmental paternal UPD of chromosome 11, which unmasks a recessively acting gain-of-function mutation in the ABCC8 gene and causes deregulation of imprinted genes at the BWS locus on 11p15.5. Diabetes 57: [255][256][257][258] 2008

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New ABCC8 Mutations in Relapsing Neonatal Diabetes and Clinical Features

Cited by 82 publications

References 24 publications

Effective Treatment With Oral Sulfonylureas in Patients With Diabetes Due to Sulfonylurea Receptor 1 (SUR1) Mutations

Effective Treatment With Oral Sulfonylureas in Patients With Diabetes Due to Sulfonylurea Receptor 1 (SUR1) Mutations

Heterozygous Missense Mutations in the Insulin Gene Are Linked to Permanent Diabetes Appearing in the Neonatal Period or in Early Infancy

Mosaic Paternal Uniparental Isodisomy and an ABCC8 Gene Mutation in a Patient With Permanent Neonatal Diabetes and Hemihypertrophy

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