Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel <i>KCNJ11 </i>gene mutation

D’Amato, Elena; Tammaro, Paolo; Craig, Timothy; Tosi, Alessandra; Giorgetti, R; Lorini, Renata; Ashcroft, Frances M.

doi:10.1111/j.1464-5491.2008.02443.x

Cited by 22 publications

(13 citation statements)

References 19 publications

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“…Some studies reported that families of patients with a transient or permanent form of NDM due to a KCNJ11 mutation can also include other carriers in the family with childhood or later-onset diabetes (age of diagnosis before 30 years) [17], [21], [22]. However, no previous study has ever described a family with a well-defined MODY due to a KCNJ11 mutation.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

et al. 2012

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BackgroundMaturity-onset of the young (MODY) is a clinically heterogeneous form of diabetes characterized by an autosomal-dominant mode of inheritance, an onset before the age of 25 years, and a primary defect in the pancreatic beta-cell function. Approximately 30% of MODY families remain genetically unexplained (MODY-X). Here, we aimed to use whole-exome sequencing (WES) in a four-generation MODY-X family to identify a new susceptibility gene for MODY.MethodologyWES (Agilent-SureSelect capture/Illumina-GAIIx sequencing) was performed in three affected and one non-affected relatives in the MODY-X family. We then performed a high-throughput multiplex genotyping (Illumina-GoldenGate assay) of the putative causal mutations in the whole family and in 406 controls. A linkage analysis was also carried out.Principal FindingsBy focusing on variants of interest (i.e. gains of stop codon, frameshift, non-synonymous and splice-site variants not reported in dbSNP130) present in the three affected relatives and not present in the control, we found 69 mutations. However, as WES was not uniform between samples, a total of 324 mutations had to be assessed in the whole family and in controls. Only one mutation (p.Glu227Lys in KCNJ11) co-segregated with diabetes in the family (with a LOD-score of 3.68). No KCNJ11 mutation was found in 25 other MODY-X unrelated subjects.Conclusions/SignificanceBeyond neonatal diabetes mellitus (NDM), KCNJ11 is also a MODY gene (‘MODY13’), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes (i.e. KCNJ11, ABCC8 and INS). Therefore, the molecular diagnosis of MODY should include KCNJ11 as affected carriers can be ideally treated with oral sulfonylureas.

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Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

et al. 2012

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“…Мутации в гене ABCC8 ассоциированы с развитием MODY 12, СД2, гестацион-ного СД и неонатального СД. Также наличие мутаций в гене ABCC8 может вызвать чрезмерную секрецию инсу-лина и, в результате, развитие гиперинсулинизма в мла-денческом возрасте [23]. Наличие мутаций в гене ABCC8 позволяет скорректировать лечение пациентов с гипер-гликемией, что связано с чувствительностью у носи-телей мутантных аллелей генов к препаратам группы сульфонилмочевины.…”

Section: Discussionunclassified

MODY in Siberia – molecular genetics and clinical characteristics

Ovsyannikova¹,

Rymar²,

Shakhtshneider³

et al. 2017

Diabetes mellitus

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Institution of Internal and Preventive Medicine, Novosibirsk, Russia The diagnosis of maturity onset diabetes of the young (MODY) has high clinical significance in young patients (no absolute need for exogenous insulin; normoglycaemia in most patients achieved by dieting or taking oral hypoglycaemic agents) and their relatives (high probability of first-degree relatives being carriers of mutations, which requires a thorough collection of family history and determination of the parameters of carbohydrate metabolism). Aim. This study aimed was to determine the clinical characteristics of different subtypes of MODY in a Siberian region. Materials and Methods. We performed an examination, biochemical and hormonal blood tests, ultrasound and molecular genetic testing of 20 patients with a clinical diagnosis of MODY.Results. Four subtypes of MODY were verified: MODY2 in 11 patients, MODY3 in two, MODY8 in one and MODY12 in two. Eleven patients (69%) (2,3,8,12) were diagnosed in the present study, which differed in their clinical characteristics, presence of complications and treatment strategies. Our knowledge of monogenic forms of diabetes is expanding with the development in molecular genetics, but several aspects related to them require further study.

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“…In general, the more stimulatory the mutation, the greater the suppression of insulin secretion and the resulting level of hyperglycemia (Figure 3A). 68–71 The underlying molecular mechanisms for the majority of activation mutations can be tested experimentally and correlated well with their specific locations within the K ATP channel subunits as follows.…”

Section: Katp Channel Activation Mutations Underlie Ndmmentioning

confidence: 99%

The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes

Light¹

2010

PGPM

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Neonatal diabetes mellitus (NDM) is a monogenic disorder caused by mutations in genes involved in regulation of insulin secretion from pancreatic β-cells. Mutations in the KCNJ11 and ABCC8 genes, encoding the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel Kir6.2 and SUR1 subunits, respectively, are found in ∼50% of NDM patients. In the pancreatic β-cell, KATP channel activity couples glucose metabolism to insulin secretion via cellular excitability and mutations in either KCNJ11 or ABCC8 genes alter KATP channel activity, leading to faulty insulin secretion. Inactivation mutations decrease KATP channel activity and stimulate excessive insulin secretion, leading to hyperinsulinism of infancy. In direct contrast, activation mutations increase KATP channel activity, resulting in impaired insulin secretion, NDM, and in severe cases, developmental delay and epilepsy. Many NDM patients with KCNJ11 and ABCC8 mutations can be successfully treated with sulfonylureas (SUs) that inhibit the KATP channel, thus replacing the need for daily insulin injections. There is also strong evidence indicating that SU therapy ameliorates some of the neurological defects observed in patients with more severe forms of NDM. This review focuses on the molecular and cellular mechanisms of mutations in the KATP channel that underlie NDM. SU pharmacogenomics is also discussed with respect to evaluating whether patients with certain KATP channel activation mutations can be successfully switched to SU therapy.

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Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation

Cited by 22 publications

References 19 publications

Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

MODY in Siberia – molecular genetics and clinical characteristics

The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes

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