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Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward
Siobhan Bacon, Ma Peyh Kyithar, Jasmin Schmid, Syed R Rizvi, Caroline Bonner, Rolf Graf, Jochen HM Prehn, Maria M Byrne
BMC Endocrine Disorders , 2012, DOI: 10.1186/1472-6823-12-13
Abstract: We analysed serum PSP/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY), and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed.PSP/reg1A serum levels were significantly elevated in HNF1A-MODY (n?=?37) subjects compared to controls (n?=?60) (median?=?12.50?ng/ml, IQR?=?10.61-17.87?ng/ml versus median?=?10.72?ng/ml, IQR?=?8.94-12.54?ng/ml, p?=?0.0008). PSP/reg1A correlated negatively with insulin levels during OGTT, (rho?=??0.40, p?=?0.02). Interestingly we noted a significant positive correlation of PSP/reg1A with age of the HNF1A-MODY carriers (rho?=?0.40 p?=?0.02) with an age of 25?years separating carriers with low and high PSP/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP/reg1A compared to controls, however this was independent of the duration of diabetes.Our data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25?years and over. PSP/reg1A may be developed as a serum marker to detect increased beta-cell apoptosis, or its therapeutic response.
Effect of the rs2259816 polymorphism in the HNF1A gene on circulating levels of c-reactive protein and coronary artery disease (the ludwigshafen risk and cardiovascular health study)
Marcus E Kleber, Tanja B Grammer, Wilfried Renner, Winfried M?rz
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-157
Abstract: We investigated the association of the rs2259816 polymorphism in the HNF1A gene with the circulating level of C-reactive protein and the hazard of coronary artery disease in the LURIC Study cohort.Compared to CC homozygotes, the level of C-reactive protein was decreased in carriers of at least one A-allele. Each A-allele decreased CRP by approximately 15%. The odds ratio for coronary artery disease was only very slightly increased in carriers of the A-allele and this association did not reach statistical significance.In the LURIC Study cohort the A-allele of rs2259816 is associated with decreased CRP but not with coronary artery disease.C-reactive protein (CRP) is a well established biochemical marker of inflammation and has been used to predict future cardiovascular disease [1-3]. As its level is increased in patients suffering from coronary artery disease (CAD) the idea has been put forward that it might play an active role in the development of the disease. Although numerous studies have been conducted, this issue has not been finally settled yet [4-6]. Most of these studies didn't find an association between CRP and CAD [7-13] whereas a few did present some evidence in favor of this idea [14-16].A recent meta-analysis has shown that associations of CRP with ischemic vascular disease depend considerably on conventional risk factors and other markers of inflammation making a causal role of CRP in the development of CAD also unlikely [17].Genetic factors have been estimated to have a great influence on the variance in plasma CRP level [18-20]. A number of polymorphisms of the CRP gene (MIM 123260) or its promoter that act in this way have been described so far [8-11,14-16,21-32] but they only account for a minor part of the assumed heritability.Recently, polymorphisms in the HNF1A gene (also known asTCF1, MIM 142410) have been linked to the levels of C-reactive protein and coronary artery disease [33-36]. This gene encodes the transcription factor hepatocyte nuclea
Clinical features and treatment of maturity onset diabetes of the young (MODY)  [cached]
Gardner DS,Tai ES
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy , 2012,
Abstract: Daphne SL Gardner1, E Shyong Tai21Department of Endocrinology, Singapore General Hospital, 2Department of Endocrinology, National University Hospital, SingaporeAbstract: Maturity onset diabetes of the young (MODY) is a heterogeneous group of disorders that result in -cell dysfunction. It is rare, accounting for just 1%–2% of all diabetes. It is often misdiagnosed as type 1 or type 2 diabetes, as it is often difficult to distinguish MODY from these two forms. However, diagnosis allows appropriate individualized care, depending on the genetic etiology, and allows prognostication in family members. In this review, we discuss features of the common causes of MODY, as well as the treatment and diagnosis of MODY.Keywords: type 1 diabetes, type 2 diabetes, HNF1A, HNF4A, HNF1B, GCK
Diabetes Mellitus do Tipo MODY
Oliveira, Carolina S.V.;Furuzawa, Gilberto K.;Reis, André F.;
Arquivos Brasileiros de Endocrinologia & Metabologia , 2002, DOI: 10.1590/S0004-27302002000200012
Abstract: it is estimated that close to 5% of the individuals classified as having type 2 diabetes mellitus (dm) and about 10% of those considered type 1 dm (previously categorized as juvenile type) are actual carriers of a mody mutation. in this form of dm, there is evident co-segregation of some mutations and the advent of hyperglycemia, this fact having been reproduced by the study of several families of different populations. its main characteristic is being one of the few causes of dm in which the transmission of the genetic susceptibility is due to an autossomical dominant inheritance, making part of the group classified as monogenic dm, where the other members are very rare. mutations occurring in mody genes, even in the heterozygous form, lead to a profound phenotypic impact (high penetrance), in that 95% of the individual carriers of a mody mutation will be diabetic or will have altered glicemic metabolism before the age of 55 years. in this paper we approach this form of dm, emphasizing its most relevant clinical and genetic characteristics. the systematic search for mody mutations is beginning to take place regularly in many countries, and there is a tendency to add this diagnostic tool to the routine exams in the practice of diabetology.
GCK-MODY (MODY 2) Caused by a Novel p.Phe330Ser Mutation  [PDF]
Walter Bonfig,Sandra Hermanns,Katharina Warncke,Gabriele Eder,Ilse Engelsberger,Stefan Burdach,Annette Gabriele Ziegler,Peter Lohse
ISRN Pediatrics , 2011, DOI: 10.5402/2011/676549
Abstract: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes inherited as an autosomal dominant trait. The second most common cause is GCK-MODY due to heterozygous mutations in the GCK gene which impair the glucokinase function through different mechanisms such as enzymatic activity, protein stability, and increased interaction with its receptor. The enzyme normally acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. We report here a three-generation nonobese family diagnosed with diabetes. All affected family members presented with mild hyperglycemia and mostly slightly elevated hemoglobin A1c values. Genetic testing revealed a novel heterozygous T → C exchange in exon 8 of the GCK gene which resulted in a phenylalanine330 TTC → serine (TCC)/p.Phe330Ser/F330S substitution. 1. Introduction MODY is a monogenic disease which accounts for 2–5% of all diabetes cases. The most frequent form is HNF-1α-MODY (MODY type 3), which is caused by mutations in the HNF1A gene encoding hepatic nuclear factor 1α. The second most frequent form is GCK-MODY (MODY type 2), which has been shown to be the result of mutations in the GCK gene [1]. The GCK gene maps to chromosome 7p15.3-p15.1 and consists of 12 exons that encode the 465-amino-acid protein glucokinase [2, 3], which is one of four members of the hexokinase family of enzymes. It catalyzes the phosphorylation of glucose as the first step of glycolysis. Glucokinase is exclusively expressed in mammalian liver and pancreatic islet beta cells. The enzyme plays an important regulatory role in glucose metabolism. As a glucose sensor, it regulates insulin secretion in the pancreatic β-cell by changing the glucose phosphorylation rate over a range of physiological glucose concentrations (4–15?mmoL/L; [4]). GCK gene mutations can cause both hypo- and hyperglycemia. Heterozygous inactivating mutations cause GCK-MODY, which mostly presents with mild hyperglycemia and is inherited in an autosomal dominant fashion [5, 6]. Usually, no diabetes-related complications such as nephropathy or retinopathy occur in patients with GCK-MODY. Homozygous or compound heterozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes mellitus [7–11]. Heterozygous activating GCK mutations, in contrast, cause persistent hyperinsulinemic hypoglycemia of infancy [12–16]. In 1992, GCK was the first MODY gene to be linked to disease in French and UK families [5, 6]. These linkage studies were quickly followed by the identification of the first
Exome Sequencing and Genetic Testing for MODY  [PDF]
Stefan Johansson, Henrik Irgens, Kishan K. Chudasama, Janne Molnes, Jan Aerts, Francisco S. Roque, Inge Jonassen, Shawn Levy, Kari Lima, Per M. Knappskog, Graeme I. Bell, Anders Molven, P?l R. Nj?lstad
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038050
Abstract: Context Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive. Objective The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results. Research Design and Methods We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism. Results On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0–4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes. Conclusion Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized.
Metabolic Profiling in Maturity-Onset Diabetes of the Young (MODY) and Young Onset Type 2 Diabetes Fails to Detect Robust Urinary Biomarkers  [PDF]
Anna L. Gloyn, Johan H. Faber, Daniel Malmodin, Gaya Thanabalasingham, Francis Lam, Per Magne Ueland, Mark I. McCarthy, Katharine R. Owen, Dorrit Baunsgaard
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040962
Abstract: It is important to identify patients with Maturity-onset diabetes of the young (MODY) as a molecular diagnosis determines both treatment and prognosis. Genetic testing is currently expensive and many patients are therefore not assessed and are misclassified as having either type 1 or type 2 diabetes. Biomarkers could facilitate the prioritisation of patients for genetic testing. We hypothesised that patients with different underlying genetic aetiologies for their diabetes could have distinct metabolic profiles which may uncover novel biomarkers. The aim of this study was to perform metabolic profiling in urine from patients with MODY due to mutations in the genes encoding glucokinase (GCK) or hepatocyte nuclear factor 1 alpha (HNF1A), type 2 diabetes (T2D) and normoglycaemic control subjects. Urinary metabolic profiling by Nuclear Magnetic Resonance (NMR) and ultra performance liquid chromatography hyphenated to Q-TOF mass spectrometry (UPLC-MS) was performed in a Discovery set of subjects with HNF1A-MODY (n = 14), GCK-MODY (n = 17), T2D (n = 14) and normoglycaemic controls (n = 34). Data were used to build a valid partial least squares discriminate analysis (PLS-DA) model where HNF1A-MODY subjects could be separated from the other diabetes subtypes. No single metabolite contributed significantly to the separation of the patient groups. However, betaine, valine, glycine and glucose were elevated in the urine of HNF1A-MODY subjects compared to the other subgroups. Direct measurements of urinary amino acids and betaine in an extended dataset did not support differences between patients groups. Elevated urinary glucose in HNF1A-MODY is consistent with the previously reported low renal threshold for glucose in this genetic subtype. In conclusion, we report the first metabolic profiling study in monogenic diabetes and show that, despite the distinct biochemical pathways affected, there are unlikely to be robust urinary biomarkers which distinguish monogenic subtypes from T2D. Our results have implications for studies investigating metabolic profiles in complex traits including T2D.
Low Frequency Variants in the Exons Only Encoding Isoform A of HNF1A Do Not Contribute to Susceptibility to Type 2 Diabetes  [PDF]
Bahram Jafar-Mohammadi, Christopher J. Groves, Katharine R. Owen, Timothy M. Frayling, Andrew T. Hattersley, Mark I. McCarthy, Anna L. Gloyn
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006615
Abstract: Background There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8–10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1–7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8–10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D. Methodology and Principal Findings We performed targeted capillary resequencing of HNF1A exons 8–10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (≤45 years) and/or family history of T2D (≥1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9?24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected. Conclusions and Significance We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.
CD36 deficiency attenuates experimental mycobacterial infection
Michael Hawkes, Xiaoming Li, Maryanne Crockett, Angelina Diassiti, Constance Finney, Gundula Min-Oo, W Conrad Liles, Jun Liu, Kevin C Kain
BMC Infectious Diseases , 2010, DOI: 10.1186/1471-2334-10-299
Abstract: Experimental Mycobacterium bovis Bacillus Calmette-Guérin (BCG) infection in Cd36+/+ and Cd36-/- mice, and in vitro co-cultivation of M. tuberculosis, BCG and M. marinum with Cd36+/+ and Cd36-/-murine macrophages.Using an in vivo model of BCG infection in Cd36+/+ and Cd36-/- mice, we found that mycobacterial burden in liver and spleen is reduced (83% lower peak splenic colony forming units, p < 0.001), as well as the density of granulomas, and circulating tumor necrosis factor (TNF) levels in Cd36-/- animals. Intracellular growth of all three mycobacterial species was reduced in Cd36-/- relative to wild type Cd36+/+ macrophages in vitro. This difference was not attributable to alterations in mycobacterial uptake, macrophage viability, rate of macrophage apoptosis, production of reactive oxygen and/or nitrogen species, TNF or interleukin-10. Using an in vitro model designed to recapitulate cellular events implicated in mycobacterial infection and dissemination in vivo (i.e., phagocytosis of apoptotic macrophages containing mycobacteria), we demonstrated reduced recovery of viable mycobacteria within Cd36-/- macrophages.Together, these data indicate that CD36 deficiency confers resistance to mycobacterial infection. This observation is best explained by reduced intracellular survival of mycobacteria in the Cd36-/- macrophage and a role for CD36 in the cellular events involved in granuloma formation that promote early bacterial expansion and dissemination.Mycobacterium tuberculosis (M. tb) infects an estimated 2 billion people worldwide and is responsible for the most deaths annually (1.6 million/year) of any single bacterial pathogen[1]. However, only 5 to 7% of infected immunocompetent individuals develop disease during their lifetime[2], demonstrating the critical role of host factors in the control of M. tb. The histological hallmark of tuberculosis is the granuloma, composed of an inner core of activated macrophages primed for intracellular killing by surrounding
Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene  [PDF]
Amélie Bonnefond, Julien Philippe, Emmanuelle Durand, Aurélie Dechaume, Marlène Huyvaert, Louise Montagne, Michel Marre, Beverley Balkau, Isabelle Fajardy, Anne Vambergue, Vincent Vatin, Jér?me Delplanque, David Le Guilcher, Franck De Graeve, Cécile Lecoeur, Olivier Sand, Martine Vaxillaire, Philippe Froguel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037423
Abstract: Background Maturity-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. Methodology WES (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 Findings By 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/Significance Beyond 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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