Insights From Molecular Characterization of Adult Patients of Families With Multigenerational Diabetes

Pezzilli, Serena; Ludovico, Ornella; Biagini, Tommaso; Mercuri, Luana; Alberico, Federica; Lauricella, E; Dallali, Hamza; Capocefalo, Daniele; Carella, Massimo; Miccinilli, Elide; Piscitelli, Pamela; Scarale, Maria Giovanna; Mazza, Tommaso; Trischitta, Vincenzo; Prudente, Sabrina

doi:10.2337/db17-0867

Cited by 25 publications

(34 citation statements)

References 45 publications

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“…It was reported that 3% of hyperglycemic adults diagnosed as having type 2 diabetes (T2D) are affected by a multigenerational disease (Ludovico et al, 2015;Pezzilli et al, 2018). Here we first show the evidence from patients with multigenerational diabetes and two mouse models supporting the pivotal role of both human KCNH6 (Kv11.3) and mouse Kcnh6 in the regulation of insulin secretion.…”

Section: Introductionmentioning

confidence: 68%

“…We know that MODY prevalence is low, and we should be cautious to interpret KCNH6 p.P235L Mut as the cause of a new MODY Mut. Of hyperglycemic adults diagnosed as having T2D, 3% are affected by multigenerational monogenic diabetes (Ludovico et al, 2015;Pezzilli et al, 2018). Usually, these patients present with the typical of metabolic abnormalities observed in T2D.…”

Section: Discussionmentioning

confidence: 99%

“…Usually, these patients present with the typical of metabolic abnormalities observed in T2D. In these patients, age at diagnosis is older than the age of patients with MODY but younger than the age of patients with classic T2D (Ludovico et al, 2015;Pezzilli et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously conducted a three-step programmed method for the identification of yet-unknown gene mutations of maturity-onset diabetes of the young (MODY-x) (Li et al, 2016). In 2009, we identified a four-generation family with multigenerational monogenic diabetes (Ludovico et al, 2015;Pezzilli et al, 2018) from a mountain village in central China ( Figure 1A). We excluded mutations in all known high-frequency MODY-1, MODY-2, and MODY-3 genes (Horikawa et al, 1997;Vionnet et al, 1992;Yamagata et al, 1996aYamagata et al, , 1996b and K ATP -related MODY genes, including ABCC8 (MODY-12) (Bowman et al, 2012) and KCNJ11 (MODY-13) (Bonnefond et al, 2012), in the proband.…”

Section: Kcnh6 Mutation In a Four-generation Pedigreementioning

confidence: 99%

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From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

et al. 2018

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Graphical Abstract Highlights d KCNH6 regulates insulin secretion and glucose hemostasis in humans and mice d KCNH6 dysfunction causes a phenotype from hyper-to hypoinsulinemia and diabetes d KCNH6 dysfunction increases intracellular calcium levels and hyperinsulinemia d Chronic elevation of intracellular calcium causes b cell loss and hypoinsulinemia In Brief Yang et al. show that KCNH6 plays a key role in insulin secretion and glucose hemostasis in humans and mice. Dysfunction of KCNH6 results in a hyperinsulinemia phenotype in the short term and hypoinsulinemia and diabetes in the long term. SUMMARYGlucose-stimulated insulin secretion from islet b cells is mediated by K ATP channels. However, the role of non-K ATP K + channels in insulin secretion is largely unknown. Here, we show that a non-K ATP K + channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree. Kcnh6 knockout (KO) or Kcnh6 p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of b cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and b cell failure in the long term.

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Kcnh6 Mutation In a Four-generation Pedigreementioning

confidence: 99%

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From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

et al. 2018

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“…This occurs when suspected MODY cases represent other types of diabetes (e.g., type 1 or 2) that can also occur in young individuals and/or coexist with other affected family members, thus mimicking the phenotype of MODY, but with no monogenic cause. As diabetes is a relatively common disease, the existence of several affected family members does not necessarily imply an inherited cause of diabetes [31]. Furthermore, the fact that mutation-negative patients in our study were diagnosed at a later age suggests that these are less likely to be associated with a genetic cause.…”

Section: Discussionmentioning

confidence: 70%

Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations

Alvelos

Gonçalves

Coutinho

et al. 2020

JCM

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Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, p = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.

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MODY probability calculator utility in individuals' selection for genetic testing: Its accuracy and performance

Santos

Fonseca

Monteiro

et al. 2022

Endocrino Diabet & Metabol

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Introduction MODY probability calculator (MPC) represents an easy‐to‐use tool developed by Exeter University to help clinicians prioritize which individuals should be oriented to genetic testing. We aimed to assess the utility of MPC in a Portuguese cohort with early‐onset monogenic diabetes. Methods This single‐centre retrospective study enrolled 132 participants submitted to genetic testing between 2015 and 2020. Automatic sequencing and, in case of initial negative results, generation sequencing were performed. MODY probability was calculated using the probability calculator available online. Positive and negative predictive values (PPV and NPV, respectively), accuracy, sensitivity and specificity of the calculator were determined for this cohort. Results Seventy‐three individuals were included according to inclusion criteria: 20 glucokinase (GCK‐MODY); 16 hepatocyte nuclear factor 1A (HNF1A‐MODY); 2 hepatocyte nuclear factor 4A (HNF4A‐MODY) and 35 DM individuals with no monogenic mutations found. The median probability score of MODY was significantly higher in monogenic diabetes‐positive subgroup (75.5% vs. 24.2%, p < .001). The discriminative accuracy of the calculator, as expressed by area under the curve, was 75% (95% CI: 64%–85%). In our cohort, the best cut‐off value for the MODY calculator was found to be 36%, with a PPV of 74.4%, NPV of 73.5% and corresponding sensitivity and specificity of 76.2% and 71.4%, respectively. Conclusions In a highly pre‐selected group of probands qualified for genetic testing, the Exeter MODY probability calculator provided a useful tool in individuals' selection for genetic testing, with good discrimination ability under an optimal probability cut‐off of 36%. Further geographical and population adjustments are warranted for general use.

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Insights From Molecular Characterization of Adult Patients of Families With Multigenerational Diabetes

Cited by 25 publications

References 45 publications

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations

MODY probability calculator utility in individuals' selection for genetic testing: Its accuracy and performance

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