148 results on '"Hattersley, Andrew T."'
Search Results
2. The Mutated Human Gene Encoding Hepatocyte Nuclear Factor 1β Inhibits Kidney Formation in Developing Xenopus Embryos
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Wild, Wiltrud, von Strandmann, Elke Pogge, Nastos, Aristotelis, Senkel, Sabine, Lingott-Frieg, Anja, Bulman, Michael, Bingham, Coralie, Ellard, Sian, Hattersley, Andrew T., and Ryffel, Gerhart U.
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- 2000
3. Recessive Mutations in the INS Gene Result in Neonatal Diabetes through Reduced Insulin Biosynthesis
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Neonatal Diabetes International Group, Garin, Intza, Edghill, Emma L., Akerman, Ildem, Rubio-Cabezas, Oscar, Rica, Itxaso, Locke, Jonathan M., Maestro, Miguel Angel, Alshaikh, Adnan, Bundak, Ruveyde, del Castillo, Gabriel, Deeb, Asma, Deiss, Dorothee, Fernandez, Juan M., Godbole, Koumudi, Hussain, Khalid, O'Connell, Michele, Klupa, Thomasz, Kolouskova, Stanislava, Mohsin, Fauzia, Perlman, Kusiel, Sumnik, Zdenek, Rial, Jose M., Ugarte, Estibaliz, Vasanthi, Thiruvengadam, Johnstone, Karen, Flanagan, Sarah E., Martínez, Rosa, Castaño, Carlos, Patch, Ann-Marie, Fernández-Rebollo, Eduardo, Raile, Klemens, Morgan, Noel, Harries, Lorna W., Castaño, Luis, Ellard, Sian, Ferrer, Jorge, de Nanclares, Guiomar Perez, Hattersley, Andrew T., and Steiner, Donald F.
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- 2010
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4. Increased ATPase Activity Produced by Mutations at Arginine-1380 in Nucleotide-Binding Domain 2 of ABCC8 Causes Neonatal Diabetes
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de Wet, Heidi, Rees, Mathew G., Shimomura, Kenju, Aittoniemi, Jussi, Patch, Ann-Marie, Flanagan, Sarah E., Ellard, Sian, Hattersley, Andrew T., Sansom, Mark S. P., and Ashcroft, Frances M.
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- 2007
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5. Insulin Gene Mutations as a Cause of Permanent Neonatal Diabetes
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Støy, Julie, Edghill, Emma L., Flanagan, Sarah E., Ye, Honggang, Paz, Veronica P., Pluzhnikov, Anna, Below, Jennifer E., Hayes, M. Geoffrey, Cox, Nancy J., Lipkind, Gregory M., Lipton, Rebecca B., Greeley, Siri Atma W., Patch, Ann-Marie, Ellard, Sian, Steiner, Donald F., Hattersley, Andrew T., Philipson, Louis H., and Bell, Graeme I.
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- 2007
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6. ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents.
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Greeley, Siri Atma W., Polak, Michel, Njølstad, Pål R., Barbetti, Fabrizio, Williams, Rachel, Castano, Luis, Raile, Klemens, Chi, Dung Vu, Habeb, Abdelhadi, Hattersley, Andrew T., and Codner, Ethel
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GENETICS of diabetes ,DIAGNOSIS of diabetes ,DIABETES prevention ,LIPODYSTROPHY ,MOLECULAR diagnosis ,GENETICS ,GENETIC mutation ,MITOCHONDRIAL pathology ,GENETIC testing ,MEDICAL protocols ,GENOMICS ,AGE factors in disease ,GENES ,DISEASE management ,INSULIN resistance ,CHILDREN ,ADOLESCENCE - Abstract
The article presents the discussion on addition of recently described subtypes of monogenic diabetes. Topics include use of increasingly available publicly accessible information about specific variants to allow for the appropriate classification of pathogenicity of gene variants; and referral to a specialist in monogenic diabetes or an interested clinical genetics unit suggested to guide specific management considerations.
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- 2022
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7. Evaluation of Evidence for Pathogenicity Demonstrates That BLK, KLF11, and PAX4 Should Not Be Included in Diagnostic Testing for MODY.
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Laver, Thomas W., Wakeling, Matthew N., Knox, Olivia, Colclough, Kevin, Wright, Caroline F., Ellard, Sian, Hattersley, Andrew T., Weedon, Michael N., and Patel, Kashyap A.
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PROTEINS ,GENETIC mutation ,ANIMAL experimentation ,TYPE 2 diabetes ,GENES ,DIAGNOSIS ,TRANSFERASES ,RESEARCH funding ,MICROBIAL virulence - Abstract
Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants in BLK (MODY11), KLF11 (MODY7), and PAX4 (MODY9) cause MODY. We examined variant-level genetic evidence (cosegregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n = 1,227) compared with a control population (UK Biobank [n = 185,898]). For comparison we analyzed well-established causes of MODY, HNF1A, and HNF4A. The published variants in BLK, KLF11, and PAX4 showed poor cosegregation with diabetes (combined logarithm of the odds [LOD] scores ≤1.2), compared with HNF1A and HNF4A (LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95 × 10-5). Ultra-rare missense and protein-truncating variants (PTV) were not enriched in a MODY cohort compared with the UK Biobank population (PTV P > 0.05, missense P > 0.1 for all three genes) while HNF1A and HNF4A were enriched (P < 10-6). Findings of sensitivity analyses with different population cohorts supported our results. Variant and gene-level genetic evidence does not support BLK, KLF11, or PAX4 as a cause of MODY. They should not be included in MODY diagnostic genetic testing. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes.
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Hiller, Helmut, Beachy, Dawn E., Lebowitz, Joseph J., Engler, Stefanie, Mason, Justin R., Miller, Douglas R., Kusmarteva, Irina, Jacobsen, Laura M., Posgai, Amanda L., Khoshbouei, Habibeh, Oram, Richard A., Schatz, Desmond A., Hattersley, Andrew T., Bodenmiller, Bernd, Atkinson, Mark A., Nick, Harry S., Wasserfall, Clive H., and Lebowitz, Joeseph J
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TYPE 1 diabetes ,GENE expression ,GENES ,ETIOLOGY of diabetes ,DIABETES ,PANCREAS ,AUTOANTIBODIES ,RESEARCH ,GENETIC mutation ,RESEARCH methodology ,RETROSPECTIVE studies ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,GENE expression profiling - Abstract
Type 1 diabetes (T1D) has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for T1D would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by nonredundant single-gene mutations. Using a "monogenetic transcriptomic strategy," we measured the expression of these genes in human T1D, autoantibody-positive (autoantibody+), and control pancreas tissues with real-time quantitative PCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression was visualized in situ with use of immunofluorescence, RNAscope, and confocal microscopy. Two dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with T1D versus unaffected control subjects. Six of these genes also saw dysregulation in pancreata from autoantibody+ individuals at increased risk for T1D. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in T1D pancreata, including three of the four eIF2α-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the T1D disease process and likely contribute to the disorder's pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2021
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9. Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress.
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Montaser, Hossam, Patel, Kashyap A., Balboa, Diego, Ibrahim, Hazem, Lithovius, Väinö, Näätänen, Anna, Chandra, Vikash, Demir, Korcan, Acar, Sezer, Ben-Omran, Tawfeg, Colclough, Kevin, Locke, Jonathan M., Wakeling, Matthew, Lindahl, Maria, Hattersley, Andrew T., Saarimäki-Vire, Jonna, and Otonkoski, Timo
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ENDOPLASMIC reticulum ,HUMAN embryonic stem cells ,DIABETES in children ,ETIOLOGY of diabetes ,DIABETES ,NERVE growth factor ,FLOW cytometry ,RESEARCH ,GENETIC mutation ,IMMUNOHISTOCHEMISTRY ,WESTERN immunoblotting ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,ENZYME-linked immunosorbent assay ,RESEARCH funding ,POLYMERASE chain reaction ,GLUCOSE tolerance tests - Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse β-cells, its precise role in human β-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired β-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human β-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of β-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human β-cell function and demonstrate the crucial role of MANF in this process. [ABSTRACT FROM AUTHOR]
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- 2021
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10. Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated Permanent Neonatal Diabetes.
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Bowman, Pamela, Mathews, Frances, Barbetti, Fabrizio, Shepherd, Maggie H., Sanchez, Janine, Piccini, Barbara, Beltrand, Jacques, Letourneau-Freiberg, Lisa R., Polak, Michel, Greeley, Siri Atma W., Rawlins, Eamon, Babiker, Tarig, Thomas, Nicholas J., De Franco, Elisa, Ellard, Sian, Flanagan, Sarah E., Hattersley, Andrew T., Mohsin, Fauzia, Cummings, Elizabeth, and LeGault, Laurent
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METABOLIC regulation ,GLYCEMIC control ,ATTENTION-deficit hyperactivity disorder ,NEURODEVELOPMENTAL treatment ,DIABETES ,RESEARCH ,GENETIC mutation ,RESEARCH methodology ,POTASSIUM ,HYPOGLYCEMIC agents ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,RESEARCH funding ,LONGITUDINAL method - Abstract
Objective: ABCC8 mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of ABCC8-PNDM and ABCC8-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM.Research Design and Methods: We studied all 24 individuals with ABCC8-PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods.Results: Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1-13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA1c 7.2% vs. 5.7%, P = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, P = 0.04), n = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, P = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%).Conclusions: Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment. [ABSTRACT FROM AUTHOR]- Published
- 2021
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11. De Novo Mutations in Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction.
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De Franco, Elisa, Caswell, Richard, Johnson, Matthew B., Wakeling, Matthew N., Amnon Zung, Vῦ Chí Dῦng, Cȃ Thi Bích Ngọc, Goonetilleke, Rajiv, Jury, Maritza Vivanco, El-Khateeb, Mohammed, Ellard, Sian, Flanagan, Sarah E., Ron, David, Hattersley, Andrew T., Zung, Amnon, Dũng, Vũ Chí, Bích Ngọc, Cấn Thị, and Vivanco Jury, Maritza
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ETIOLOGY of diabetes ,HUMAN chromosome abnormality diagnosis ,CELLULAR control mechanisms ,NUCLEOTIDE sequencing ,GENETIC disorders ,PROTEIN metabolism ,COMPARATIVE studies ,COMPUTER simulation ,DIABETES ,LIVER diseases ,MATHEMATICAL models ,RESEARCH methodology ,MEDICAL cooperation ,GENETIC mutation ,PROTEINS ,RESEARCH ,PHYSIOLOGICAL stress ,DISEASE relapse ,THEORY ,EVALUATION research ,SEQUENCE analysis - Abstract
Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1's fundamental role within this pathway. [ABSTRACT FROM AUTHOR]
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- 2020
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12. Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated.
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Johnson, Matthew B., De Franco, Elisa, Greeley, Siri Atma W., Letourneau, Lisa R., Gillespie, Kathleen M., Wakeling, Matthew N., Ellard, Sian, Flanagan, Sarah E., Patel, Kashyap A., Hattersley, Andrew T., and International DS-PNDM Consortium
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DOWN syndrome ,TRISOMY 18 syndrome ,TYPE 1 diabetes ,DIABETES in children ,PEOPLE with Down syndrome ,DIABETES ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,GENETIC mutation ,RESEARCH ,EVALUATION research ,SEQUENCE analysis ,DISEASE complications - Abstract
Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into β-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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13. ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents.
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Hattersley, Andrew T., Greeley, Siri A. W., Polak, Michel, Rubio‐Cabezas, Oscar, Njølstad, Pål R., Mlynarski, Wojciech, Castano, Luis, Carlsson, Annelie, Raile, Klemens, Chi, Dung V., Ellard, Sian, and Craig, Maria E.
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GENETICS of diabetes , *TYPE 2 diabetes diagnosis , *TYPE 2 diabetes treatment , *HYPERGLYCEMIA , *TREATMENT of diabetes , *TYPE 1 diabetes , *INSULIN resistance , *KIDNEY diseases , *LAURENCE-Moon-Biedl syndrome , *MEDICAL protocols , *GENETIC mutation , *PROFESSIONAL associations , *GENETIC testing , *ALSTROM syndrome , *WOLFRAM syndrome , *LIPODYSTROPHY , *GENETICS , *DIAGNOSIS - Abstract
The article focuses on the International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines on diagnosis and management of monogenic diabetes in children and adolescents. It mentions that molecular genetic diagnosis of neonatal diabetes will give information on which patients have a potassium channel mutation and can be treated with high dose sulfonylureas and which patients have transient neonatal diabetes mellitus. Also discussed are specific subtypes of monogenic diabetes.
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- 2018
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14. The Common Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY.
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Locke, Jonathan M., Saint-Martin, Cécile, Laver, Thomas W., Patel, Kashyap A., Wood, Andrew R., Sharp, Seth A., Ellard, Sian, Bellanné-Chantelot, Christine, Hattersley, Andrew T., Harries, Lorna W., and Weedon, Michael N.
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METABOLIC disorders ,CARBOHYDRATE intolerance ,ENDOCRINE diseases ,NUTRITION disorders ,OBESITY ,GLUCOSE metabolism disorders ,TYPE 2 diabetes ,PROTEIN metabolism ,AGE factors in disease ,ALLELES ,AMINO acids ,DATABASES ,DISEASE susceptibility ,GENES ,GENETIC polymorphisms ,GENETIC techniques ,LONGITUDINAL method ,META-analysis ,GENETIC mutation ,PROTEINS ,RESEARCH evaluation ,SEQUENCE analysis - Abstract
There is wide variation in the age at diagnosis of diabetes in individuals with maturity-onset diabetes of the young (MODY) due to a mutation in the HNF1A gene. We hypothesized that common variants at the HNF1A locus (rs1169288 [I27L], rs1800574 [A98V]), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in individuals with HNF1A-MODY. Meta-analysis of two independent cohorts, comprising 781 individuals with HNF1A-MODY, found no significant associations between genotype and age at diagnosis. However after stratifying according to type of mutation (protein-truncating variant [PTV] or missense), we found each 27L allele to be associated with a 1.6-year decrease (95% CI -2.6, -0.7) in age at diagnosis, specifically in the subset (n = 444) of individuals with a PTV. The effect size was similar and significant across the two independent cohorts of individuals with HNF1A-MODY. We report a robust genetic modifier of HNF1A-MODY age at diagnosis that further illustrates the strong effect of genetic variation within HNF1A upon diabetes phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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15. Recessively Inherited Mutations Cause Autoimmunity Presenting as Neonatal Diabetes.
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Johnson, Matthew B., De Franco, Elisa, Lango Allen, Hana, Al Senani, Aisha, Elbarbary, Nancy, Siklar, Zeynep, Berberoglu, Merih, Imane, Zineb, Haghighi, Alireza, Razavi, Zahra, Ullah, Irfan, Alyaarubi, Saif, Gardner, Daphne, Ellard, Sian, Hattersley, Andrew T., and Flanagan, Sarah E.
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AUTOIMMUNE diseases ,DIABETES ,AUTOIMMUNITY ,MONOGENIC & polygenic inheritance (Genetics) ,EXOMES ,LYMPHOPROLIFERATIVE disorders ,CARRIER proteins ,CONSANGUINITY ,DISEASE susceptibility ,GENEALOGY ,GENES ,GENETIC techniques ,IMMUNITY ,TYPE 1 diabetes ,GENETIC mutation ,RESEARCH funding - Abstract
Young-onset autoimmune diabetes associated with additional autoimmunity usually reflects a polygenic predisposition, but rare cases result from monogenic autoimmunity. Diagnosing monogenic autoimmunity is crucial for patients' prognosis and clinical management. We sought to identify novel genetic causes of autoimmunity presenting with neonatal diabetes (NDM) (diagnosis <6 months). We performed exome sequencing in a patient with NDM and autoimmune lymphoproliferative syndrome and his unrelated, unaffected parents and identified compound heterozygous null mutations in LRBA Biallelic LRBA mutations cause common variable immunodeficiency-8; however, NDM has not been confirmed in this disorder. We sequenced LRBA in 169 additional patients with diabetes diagnosed <1 year without mutations in the 24 known NDM genes. We identified recessive null mutations in 8 additional probands, of which, 3 had NDM (<6 months). Diabetes was the presenting feature in 6 of 9 probands. Six of 17 (35%) patients born to consanguineous parents and with additional early-onset autoimmunity had recessive LRBA mutations. LRBA testing should be considered in patients with diabetes diagnosed <12 months, particularly if they have additional autoimmunity or are born to consanguineous parents. A genetic diagnosis is important as it can enable personalized therapy with abatacept, a CTLA-4 mimetic, and inform genetic counseling. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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16. Dominant ER Stress-Inducing Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.
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De Franco, Elisa, Flanagan, Sarah E., Takuya Yagi, Abreu, Damien, Mahadevan, Jana, Johnson, Matthew B., Jones, Garan, Acosta, Fernanda, Mulaudzi, Mphele, Ngee Lek, Oh, Vera, Petz, Oliver, Caswell, Richard, Ellard, Sian, Fumihiko Urano, Hattersley, Andrew T., Yagi, Takuya, Lek, Ngee, and Urano, Fumihiko
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NEONATAL diseases ,DIABETES in children ,PEDIATRIC endocrinology ,ENDOPLASMIC reticulum ,ORGANELLES ,CATARACT ,SENSORINEURAL hearing loss ,DIABETES ,IMMUNOBLOTTING ,MEMBRANE proteins ,MUSCLE hypotonia ,GENETIC mutation ,RESEARCH funding ,SYNDROMES ,PHENOTYPES ,GENETIC carriers ,WOLFRAM syndrome ,IN vitro studies - Abstract
Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome-causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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17. The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.
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Laver, Thomas W., Colclough, Kevin, Shepherd, Maggie, Patel, Kashyap, Houghton, Jayne A. L., Dusatkova, Petra, Pruhova, Stepanka, Morris, Andrew D., Palmer, Colin N., McCarthy, Mark I., Ellard, Sian, Hattersley, Andrew T., and Weedon, Michael N.
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TYPE 2 diabetes ,HEPATOCYTE nuclear factors ,SULFONYLUREAS ,GENETIC carriers ,PREGNANCY ,MANAGEMENT ,HYPOGLYCEMIC agents ,BIRTH weight ,CELL receptors ,DISEASE susceptibility ,GENETIC mutation ,RESEARCH funding ,BIOINFORMATICS ,HAPLOTYPES ,ODDS ratio ,THERAPEUTICS - Abstract
HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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18. Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation.
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Houghton, Jayne A. L., Swift, Galvin H., Shaw-Smith, Charles, Flanagan, Sarah E., de Franco, Elisa, Caswell, Richard, Hussain, Khalid, Mohamed, Sarar, Abdulrasoul, Majedah, Hattersley, Andrew T., MacDonald, Raymond J., and Ellard, Sian
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GENETIC transcription ,GENETIC code ,DIABETES ,NUCLEOTIDES ,GENETIC polymorphisms ,ELECTROPHORESIS ,GENETIC mutation ,PANCREAS ,RESEARCH funding ,TRANSCRIPTION factors ,SEQUENCE analysis ,GENOTYPES - Abstract
Homozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome-wide single nucleotide polymorphism typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next-generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All four patients were diagnosed with diabetes at birth and were treated with insulin. Two of the four patients had exocrine pancreatic insufficiency requiring replacement therapy but none of the affected individuals had neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts the severity of clinical features found in patients. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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19. Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes.
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Patel, Kashyap A., Oram, Richard A., Flanagan, Sarah E., De Franco, Elisa, Colclough, Kevin, Shepherd, Maggie, Ellard, Sian, Weedon, Michael N., Hattersley, Andrew T., Patel, K A, Oram, R A, Flanagan, S E, De Franco, E, Colclough, K, Shepherd, M, Ellard, S, Weedon, M N, and Hattersley, A T
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GENETICS of diabetes ,TYPE 1 diabetes ,HEMOGLOBIN polymorphisms ,AUTOIMMUNE diseases ,BIOMARKERS ,TYPE 2 diabetes diagnosis ,DIFFERENTIAL diagnosis ,DISEASE susceptibility ,GENETIC mutation ,TYPE 2 diabetes ,RESEARCH funding ,GENOTYPES ,DIAGNOSIS - Abstract
Distinguishing patients with monogenic diabetes from those with type 1 diabetes (T1D) is important for correct diagnosis, treatment, and selection of patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating characteristic area under the curve 0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS of 242 white European patients with neonatal diabetes (NDM) who had been tested for all known NDM genes. Monogenic NDM was confirmed in 90, 59, and 8% of patients with GRS <5th T1D centile, 50-75th T1D centile, and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cutoff in 48 NDM patients with no known genetic cause identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later and had less syndromic presentation but additional autoimmune features compared with those with proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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20. Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus.
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Sansbury, Francis H, Kirel, Birgül, Caswell, Richard, Lango Allen, Hana, Flanagan, Sarah E, Hattersley, Andrew T, Ellard, Sian, and Shaw-Smith, Charles J
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GENETICS of diabetes ,GENETIC mutation ,X-linked genetic disorders ,TRANSCRIPTION factors ,HETEROZYGOSITY ,HUMAN genetics - Abstract
Neonatal diabetes is a highly genetically heterogeneous disorder. There are over 20 distinct syndromic and non-syndromic forms, including dominant, recessive and X-linked subtypes. Biallelic truncating or mis-sense mutations in the DNA-binding domain of the RFX6 transcription factor cause an autosomal recessive, syndromic form of neonatal diabetes previously described as Mitchell-Riley syndrome. In all, eight cases have been reported, with the age at onset of diabetes in the first 2 weeks of life. Here we report two individuals born to double first cousins in whom intestinal atresias consistent with a diagnosis of Mitchell-Riley syndrome were diagnosed at birth, but in whom diabetes did not present until the ages of 3 and 6 years. Novel compound heterozygous RFX6 nonsense mutations (p.Arg726X/p.Arg866X) were identified at the 3′ end of the gene. The later onset of diabetes in these patients may be due to incomplete inactivation of RFX6. Genetic testing for RFX6 mutations should be considered in patients presenting with intestinal atresias in the absence of neonatal diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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21. A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.
- Author
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Abdulkarim, Baroj, Nicolino, Marc, Igoillo-Esteve, Mariana, Daures, Mathilde, Romero, Sophie, Philippi, Anne, Senée, Valérie, Lopes, Miguel, Cunha, Daniel A., Harding, Heather P., Derbois, Céline, Bendelac, Nathalie, Hattersley, Andrew T., Eizirik, Décio L., Ron, David, Cnop, Miriam, and Julier, Cécile
- Subjects
MISSENSE mutation ,DIABETES ,MICROCEPHALY ,SHORT stature ,ENDOPLASMIC reticulum ,PHOSPHORYLATION ,PANCREATIC beta cells ,DEPHOSPHORYLATION ,ESTERASES ,GROWTH disorders ,GENETIC mutation ,RESEARCH funding ,SYNDROMES ,CRANIOFACIAL abnormalities - Abstract
Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) are associated with pancreatic β-cell failure and diabetes. Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2α phosphorylation [CReP]) encoding the regulatory subunit of an eIF2α-specific phosphatase in two siblings affected by a novel syndrome of diabetes of youth with short stature, intellectual disability, and microcephaly. The R658C mutation in PPP1R15B affects a conserved amino acid within the domain important for protein phosphatase 1 (PP1) binding. The R658C mutation decreases PP1 binding and eIF2α dephosphorylation and results in β-cell apoptosis. Our findings support the concept that dysregulated eIF2α phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the phosphatase (PPP1R15B), is deleterious to β-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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22. Comment on Dubois-Laforgue et al. Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B ( ) Molecular Defects. Diabetes Care 2017;40:1436-1443.
- Author
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Clissold, Rhian L., Harries, Lorna W., Ellard, Sian, Bingham, Coralie, Hattersley, Andrew T., Dubois-Laforgue, Danièle, Cornu, Erika, Saint-Martin, Cécile, Coste, Jöel, Bellanné-Chantelot, Christine, and Timsit, José
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DIABETES ,HEPATOCYTE nuclear factors ,DIABETIC nephropathies ,PROGNOSIS ,COMPARATIVE studies ,GENETIC techniques ,RESEARCH methodology ,MEDICAL cooperation ,GENETIC mutation ,TYPE 2 diabetes ,PROTEINS ,RESEARCH ,RESEARCH funding ,PHENOTYPES ,EVALUATION research ,GENOTYPES - Published
- 2018
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23. The value of in vitro studies in a case of neonatal diabetes with a novel Kir6.2-W68G mutation.
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O'Connell, Susan M., Proks, Peter, Kramer, Holger, Mattis, Katia K., Sachse, Gregor, Joyce, Caroline, Houghton, Jayne A. L., Ellard, Sian, Hattersley, Andrew T., Ashcroft, Frances M., and O'Riordan, Stephen M. P.
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PEOPLE with diabetes ,NEWBORN infant health ,GENETIC mutation ,POTASSIUM channels ,SULFONYLUREAS ,IN vitro studies ,THERAPEUTICS - Abstract
Key Clinical Message In infants, especially with novel previously undescribed mutations of the K
ATP channel causing neonatal diabetes, in vitro studies can be used to both predict the response to sulphonylurea treatment and support a second trial of glibenclamide at higher than standard doses if the expected response is not observed. [ABSTRACT FROM AUTHOR]- Published
- 2015
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24. Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations.
- Author
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Demirbilek, Huseyin, Arya, Ved Bhushan, Ozbek, Mehmet Nuri, Houghton, Jayne A. L., Baran, Riza Taner, Akar, Melek, Tekes, Selahattin, Tuzun, Heybet, Mackay, Deborah J., Flanagan, Sarah E., Hattersley, Andrew T., Ellard, Sian, and Hussain, Khalid
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DIABETES in children ,POTASSIUM channels ,ADENOSINE triphosphate ,GENETIC mutation ,GLUCOKINASE ,CHILDREN ,NEWBORN infant health - Abstract
Background: Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey. Design and Methods:NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed. Results:Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (nZ3), ABCC8 (nZ1) and homozygous INS (nZ1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (nZ6), EIF2AK3 (nZ3), PTF1A (nZ3), and INS (nZ1) and heterozygous KCNJ11 (nZ2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331COA INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births. Conclusions:Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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25. The diagnosis and management of monogenic diabetes in children and adolescents.
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Rubio ‐ Cabezas, Oscar, Hattersley, Andrew T, Njølstad, Pål R, Mlynarski, Wojciech, Ellard, Sian, White, Neil, Chi, Dung Vu, and Craig, Maria E
- Subjects
- *
DIAGNOSIS of diabetes , *PATIENT selection , *TYPE 1 diabetes , *DIABETES , *ENDOCRINOLOGY , *GENES , *MOLECULAR diagnosis , *GENETIC mutation , *PEDIATRICS , *DISEASE management , *DIAGNOSIS - Abstract
The article presents a part of the guidelines on pediatric diabetes in the International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines 2014 Compedium. It highlights the recommendations for diagnosis and management of monogenic diabetes in children and adolescents. It features the similar grading system used in the ISPAD guidelines with that of the American Diabetes Association.
- Published
- 2014
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26. Permanent neonatal diabetes in siblings with novel C109Y INS mutation transmitted by an unaffected parent with somatic mosaicism.
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Bee, Yong Mong, Zhao, Yi, Ellard, Sian, Hattersley, Andrew T, and Yap, Fabian
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GENETICS of diabetes ,DNA ,GENETIC testing ,DIABETES ,PEOPLE with diabetes ,GENEALOGY ,GENES ,GENETIC disorders ,GENETICS ,GENETIC techniques ,MOLECULAR biology ,GENETIC mutation ,PARENTS ,PEDIATRICS ,POLYMERASE chain reaction ,PHYSIOLOGY - Abstract
Mutations involving the insulin ( INS) gene are a common cause of permanent neonatal diabetes ( PND). Although INS mutations typically occur de novo and germline INS mutations transmitted to offspring by unaffected parents has been described, somatic mosaicism in a parent with an INS mutation has not been previously reported. We describe two siblings (one brother and one sister) with PND (26- and 19-yr old diagnosed at 3 and 7 months old, respectively), whose parents were unaffected. We performed genetic analysis of leukocyte DNA for this family. Both patients were found to carry the novel heterozygous c. 326G>A substitution in exon 3 of INS, resulting in a p. C109Y change of the insulin protein. Analyses of leukocyte DNA from the parents revealed low level mutation in the sequencing trace of the father, raising the possibility of somatic mosaicism. Real-time polymerase chain reaction ( PCR) analysis showed he had approximately 73% of the mutant allele relative to his affected son. This first report of somatic mosaicism in an unaffected parent with an INS mutation suggests that parental mosaicism may be responsible for the transmission of PND in patients with de novo INS mutations. As such, appropriate counseling for recurrent risks should be considered and we recommend that molecular genetic testing for future siblings at birth should be offered to the parents of children with INS mutation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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27. The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype.
- Author
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Hamilton, Alexander J., Bingham, Coralie, McDonald, Timothy J., Cook, Paul R., Caswell, Richard C., Weedon, Michael N., Oram, Richard A., Shields, Beverley M., Shepherd, Maggie, Inward, Carol D., Hamilton-Shield, Julian P., Kohlhase, Jürgen, Ellard, Sian, and Hattersley, Andrew T.
- Subjects
FANCONI syndrome ,PHENOTYPES ,GENETIC mutation ,HYPERINSULINISM ,PANCREATIC beta cells ,GENETICS - Abstract
Background Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. Methods and Results We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. Conclusions The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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28. Prevalence of Vascular Complications Among Patients With Glucoldnase Mutations and Prolonged, Mild Hyperglycemia.
- Author
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Steele, Anna M., Shields, Beverley M., Wensley, Kirsty J., Colclough, Kevin, Ellard, Sian, and Hattersley, Andrew T.
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GLYCEMIC index ,PREVENTION of diabetes complications ,GLUCOKINASE ,GLYCOSYLATED hemoglobin ,GENETIC mutation ,TYPE 2 diabetes - Abstract
IMPORTANCE Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA
lc ) level that mimics recommended levels for type 1 and type 2 diabetes. OBJECTIVE To assess the association between chronic, mild hyperglycemia and complication prevalence and severity in patients with GCK mutations. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study in the United Kingdom between August 2008 and December 2010. Assessment of microvascular and macrovascular complications in participants 35 years or older was conducted in 99 GCK mutation carriers (median age, 48.6 years), 91 nondiabetic, familial, nonmutation carriers (control) (median age, 52.2 years), and 83 individuals with young-onset type 2 diabetes (YT2D), diagnosed at age 45 years or younger (median age, 54.7 years). MAIN OUTCOMES AND MEASURES Prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease, and cardiovascular disease. RESULTS Median HbAlc was 6.9% in patients with the GCK mutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients with GCK had a low prevalence of clinically significant microvascular complications (1% [95% Cl, 0%-5%]) that was not significantly different from controls (2% [95% Cl, 0.3%-8%], P=.52) and lower than in patients with YT2D (36% [95% Cl, 25%-47%], P<.001). Thirty percent of patients with GCK had retinopathy (95% Cl, 21%-41%) compared with 14% of controls (95% Cl. 7%-23%, P=.007) and 63% of patients with YT2D (95% Cl, 51%-73%, P<.001). Neither patients with GCK nor controls required laser therapy for retinopathy compared with 28% (95% Cl, 18%-39%) of patients with YT2D (P<.001). Neither patients with GCK patients nor controls had proteinuria and microalbuminuria was rare (GCK, 1% [95% Cl, 0.2%-6%]; controls, 2% [95% Cl, 0.2%-8%]), whereas 10% (95% Cl, 4%-19%) of YT2D patients had proteinuria (P<.001 vs G00 and 21% (95% Cl, 13%-32%) had microalbuminuria (P<.001). Neuropathy was rare in patients with GCK (2% [95% Cl, 0.3%-8%]) and controls (95% Cl, 0% [0%-4%]) but present in 29% (95% Cl, 20%-50%) of YT2D patients (P<.001). Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% Cl, 1%-10%]) that was not significantly different from controls (11% [95% Cl, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% Cl. 21%-41%], P<.001). CONCLUSIONS AND RELEVANCE Despite a median duration of 48.6 years of hyperglycemia, patients with a GCK mutation had low prevalence of microvascular and macrovascular complications. These findings may provide insights into the risks associated with isolated, mild hyperglycemia. [ABSTRACT FROM AUTHOR]- Published
- 2014
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29. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.
- Author
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Weedon, Michael N, Cebola, Inês, Patch, Ann-Marie, Flanagan, Sarah E, De Franco, Elisa, Caswell, Richard, Rodríguez-Seguí, Santiago A, Shaw-Smith, Charles, Cho, Candy H-H, Allen, Hana Lango, Houghton, Jayne A L, Roth, Christian L, Chen, Rongrong, Hussain, Khalid, Marsh, Phil, Vallier, Ludovic, Murray, Anna, Ellard, Sian, Ferrer, Jorge, and Hattersley, Andrew T
- Subjects
GENETIC mutation ,PANCREATIC diseases ,HUMAN abnormalities ,EMBRYONIC stem cells ,DEVELOPMENTAL biology ,NUCLEOTIDE sequence - Abstract
The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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30. Use of HbA1c in the Identification of Patients with Hyperglycaemia Caused by a Glucokinase Mutation: Observational Case Control Studies.
- Author
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Steele, Anna M., Wensley, Kirsty J., Ellard, Sian, Murphy, Rinki, Shepherd, Maggie, Colclough, Kevin, Hattersley, Andrew T., and Shields, Beverley M.
- Subjects
HYPERGLYCEMIA ,RECEIVER operating characteristic curves ,ETIOLOGY of diseases ,GLUCOKINASE ,GENETIC mutation ,SCIENTIFIC observation ,BLOOD sugar - Abstract
Aims: HaemoglobinA1c (HbA1c) is recommended for diabetes diagnosis but fasting plasma glucose (FPG) has been useful for identifying patients with glucokinase (GCK) mutations which cause lifelong persistent fasting hyperglycaemia. We aimed to derive age-related HbA1c reference ranges for these patients to determine how well HbA1c can discriminate patients with a GCK mutation from unaffected family members and young-onset type 1 (T1D) and type 2 diabetes (T2D) and to investigate the proportion of GCK mutation carriers diagnosed with diabetes using HbA1c and/or FPG diagnostic criteria. Methods: Individuals with inactivating GCK mutations (n = 129), familial controls (n = 100), T1D (n = 278) and T2D (n = 319) aged ≥18years were recruited. Receiver Operating Characteristic (ROC) analysis determined effectiveness of HbA1c and FPG to discriminate between groups. Results: HbA1c reference ranges in subjects with GCK mutations were: 38–56 mmol/mol (5.6–7.3%) if aged ≤40years; 41–60 mmol/mol (5.9–7.6%) if >40years. All patients (123/123) with a GCK mutation were above the lower limit of the HbA1c age-appropriate reference ranges. 69% (31/99) of controls were below these lower limits. HbA1c was also effective in discriminating those with a GCK mutation from those with T1D/T2D. Using the upper limit of the age-appropriate reference ranges to discriminate those with a mutation from those with T1D/T2D correctly identified 97% of subjects with a mutation. The majority (438/597 (73%)) with other types of young-onset diabetes had an HbA1c above the upper limit of the age-appropriate GCK reference range. HbA1c ≥48 mmol/mol classified more people with GCK mutations as having diabetes than FPG ≥7 mmol/l (68% vs. 48%, p = 0.0009). Conclusions: Current HbA1c diagnostic criteria increase diabetes diagnosis in patients with a GCK mutation. We have derived age-related HbA1c reference ranges that can be used for discriminating hyperglycaemia likely to be caused by a GCK mutation and aid identification of probands and family members for genetic testing. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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31. Gain-of-Function Mutations in the KATP Channel (KCNJ11) Impair Coordinated Hand-Eye Tracking.
- Author
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McTaggart, James S., Jenkinson, Ned, Brittain, John-Stuart, Greeley, Siri A. W., Hattersley, Andrew T., and Ashcroft, Frances M.
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GENETIC mutation ,ADENOSINE triphosphate ,POTASSIUM channels ,DIABETES in children ,SENSORY perception ,ENDOCRINOLOGY ,LABORATORY mice - Abstract
Background: Gain-of-function mutations in the ATP-sensitive potassium channel can cause permanent neonatal diabetes mellitus (PNDM) or neonatal diabetes accompanied by a constellation of neurological symptoms (iDEND syndrome). Studies of a mouse model of iDEND syndrome revealed that cerebellar Purkinje cell electrical activity was impaired and that the mice exhibited poor motor coordination. In this study, we probed the hand-eye coordination of PNDM and iDEND patients using visual tracking tasks to see if poor motor coordination is also a feature of the human disease. Methods: Control participants (n = 14), patients with iDEND syndrome (n = 6 or 7), and patients with PNDM (n = 7) completed three computer-based tasks in which a moving target was tracked with a joystick-controlled cursor. Patients with PNDM and iDEND were being treated with sulphonylurea drugs at the time of testing. Results: No differences were seen between PNDM patients and controls. Patients with iDEND syndrome were significantly less accurate than controls in two of the three tasks. The greatest differences were seen when iDEND patients tracked blanked targets, i.e. when predictive tracking was required. In this task, iDEND patients incurred more discrepancy errors (p = 0.009) and more velocity errors (p = 0.009) than controls. Conclusions: These results identify impaired hand-eye coordination as a new clinical feature of iDEND. The aetiology of this feature is likely to involve cerebellar dysfunction. The data further suggest that sulphonylurea doses that control the diabetes of these patients may be insufficient to fully correct their neurological symptoms. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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32. GATA6 Mutations Cause a Broad Phenotypic Spectrum of Diabetes From Pancreatic Agenesis to Adult-Onset Diabetes Without Exocrine Insufficiency.
- Author
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De Franco, Elisa, Shaw-Smith, Charles, Flanagan, Sarah E., Shepherd, Maggie H., Hattersley, Andrew T., and Ellard, Sian
- Subjects
EXOCRINE glands ,GENETIC mutation ,PANCREAS ,INSULIN ,DIABETES - Abstract
We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12-46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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33. Early-onset, severe lipoatrophy in a patient with permanent neonatal diabetes mellitus secondary to a recessive mutation in the INS gene.
- Author
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Rachmiel, Marianna, Rubio-Cabezas, Oscar, Ellard, Sian, Hattersley, Andrew T, and Perlman, Kusiel
- Subjects
SKIN disease diagnosis ,DNA ,ADIPOSE tissues ,AGE factors in disease ,HUMAN body composition ,CONSANGUINITY ,DIABETES ,PEOPLE with diabetes ,GENEALOGY ,GENES ,GENETIC techniques ,GLYCOSYLATED hemoglobin ,HYPOGLYCEMIC agents ,MOLECULAR biology ,GENETIC mutation ,PHYSIOLOGY - Abstract
Rachmiel M, Rubio-Cabezas O, Ellard S, Hattersley AT, Perlman K. Early-onset, severe lipoatrophy in a patient with permanent neonatal diabetes mellitus secondary to a recessive mutation in the INS gene. We describe a case of neonatal diabetes due to a homozygous mutation (c.3 G>T) at the INS gene, leading to lack of insulin expression and severe hyperglycemia from day one of life requiring permanent insulin replacement therapy. The genetic loss of endogenous insulin production likely led to lack of immune tolerance to insulin, with resultant autoantibody production against exogenous insulin and progressive immune-mediated lipoatrophy at injection sites. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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34. Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes.
- Author
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Fraser, Clementine S., Rubio-Cabezas, Oscar, Littlechild, Jennifer A., Ellard, Sian, Hattersley, Andrew T., and Flanagan, Sarah E.
- Subjects
DIABETES in children ,AMINO acids ,HEALTH outcome assessment ,PHENOTYPES ,GENETIC mutation ,STATISTICAL correlation - Abstract
Background: Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the b-cell KATP channel, are a common cause of neonatal diabetes. The diabetes may be permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus (TNDM), and in ∼20% of patients, neurological features are observed. A correlation between the position of the mutation in the protein and the clinical phenotype has previously been described; however, recently, this association has become less distinct with different mutations at the same residues now reported in patients with different diabetic and/or neurological phenotypes. Methods:We identified from the literature, and our unpublished series, KCNJ11 mutations that affected residues harbouring various amino acid substitutions (AAS) causing differences in diabetic or neurological status. Using the Grantham amino acid scoring system, we investigated whether the difference in properties between the wild-type and the different AAS at the same residue could predict phenotypic severity. Results: Pair-wise analysis demonstrated higher Grantham scores for mutations causing PNDM or diabetes with neurological features when compared with mutations affecting the same residue that causes TNDM (P=0.013) or diabetes without neurological features (P=0.016) respectively. In just five of the 25 pair-wise analyses, a lower Grantham score was observed for the more severe phenotype. In each case, the wild-type residue was glycine, the simplest amino acid. Conclusion: This study demonstrates the importance of the specific AAS in determining phenotype and highlights the potential utility of the Grantham score for predicting phenotypic severity for novel KCNJ11 mutations affecting previously mutated residues. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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35. Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia.
- Author
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Shaw-Smith, Charles, Flanagan, Sarah E, Patch, Ann-Marie, Grulich-Henn, Juergen, Habeb, Abdelhadi M, Hussain, Khalid, Pomahacova, Renata, Matyka, Krystyna, Abdullah, Mohamed, Hattersley, Andrew T, and Ellard, Sian
- Subjects
DIAGNOSIS of diabetes ,MACROCYTIC anemia ,DIABETES ,GENE amplification ,GENES ,GENETICS ,GENETIC mutation ,PEDIATRICS ,DIAGNOSIS ,VITAMIN B1 ,THERAPEUTICS ,VITAMIN therapy - Abstract
Permanent neonatal diabetes mellitus ( PNDM) is diagnosed within the first 6 months of life, and is usually monogenic in origin. Heterozygous mutations in ABCC8, KCNJ11, and INS genes account for around half of cases of PNDM; mutations in 10 further genes account for a further 10%, and the remaining 40% of cases are currently without a molecular genetic diagnosis. Thiamine-responsive megaloblastic anaemia ( TRMA), due to mutations in the thiamine transporter SLC19 A2, is associated with the classical clinical triad of diabetes, deafness, and megaloblastic anaemia. Diabetes in this condition is well described in infancy but has only very rarely been reported in association with neonatal diabetes. We used a combination of homozygosity mapping and evaluation of clinical information to identify cases of TRMA from our cohort of patients with PNDM. Homozygous mutations in SLC19 A2 were identified in three cases in which diabetes presented in the first 6 months of life, and a further two cases in which diabetes presented between 6 and 12 months of age. We noted the presence of a significant neurological disorder in four of the five cases in our series, prompting us to examine the incidence of these and other non-classical clinical features in TRMA. From 30 cases reported in the literature, we found significant neurological deficit (stroke, focal, or generalized epilepsy) in 27%, visual system disturbance in 43%, and cardiac abnormalities in 27% of cases. TRMA should be considered in the differential diagnosis of diabetes presenting in the neonatal period. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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36. KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life.
- Author
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Rubio-Cabezas, Oscar, Flanagan, Sarah E, Damhuis, Annet, Hattersley, Andrew T, and Ellard, Sian
- Subjects
TYPE 1 diabetes ,ADENOSINE triphosphate ,AGE factors in disease ,DIABETES ,GENES ,GENETICS ,GENETIC mutation ,PEDIATRICS ,POTASSIUM ,DIAGNOSIS - Abstract
Background/Objective Mutations in the K
ATP channel genes are the commonest cause of permanent neonatal diabetes. Most patients obtain optimal glycemic control on sulfonylurea treatment. Genetic testing is currently recommended for all infants diagnosed before 6 months of age. We aimed to explore the prevalence of KATP channel diabetes in infants presenting between 6 and 12 months. Methods The KCNJ11 and ABCC8 genes were sequenced in 115 infants with permanent diabetes diagnosed between 6 and 12 months and in 405 patients presenting before 6 months. Results Mutations in either gene were identified in 197 patients diagnosed before 6 months (48.6%), three infants diagnosed between 6 and 9 months (4.2%) and none of those diagnosed after 9 months. Two patients diagnosed after 6 months were successfully transferred from insulin to sulfonylureas. Conclusion KATP channel mutations are an uncommon cause of diabetes in infants presenting after 6 months. However, given the potential clinical benefit from identifying a KATP channel mutation, we recommend that KATP mutation testing should be routinely extended to infants diagnosed up to 9 months. [ABSTRACT FROM AUTHOR]- Published
- 2012
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37. A conserved tryptophan at the membrane-water interface acts as a gatekeeper for Kir6.2/SUR1 channels and causes neonatal diabetes when mutated.
- Author
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Männikkö, Roope, Stansfeld, Phillip J., Ashcroft, Alexandra S., Hattersley, Andrew T., Sansom, Mark S. P., Ellard, Sian, and Ashcroft, Frances M.
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ADENOSINE triphosphate ,POTASSIUM channels ,DIABETES in children ,GENETIC mutation ,TRYPTOPHAN - Abstract
The article focuses on a study on whether W68R, a new heterozygous mutation in the Kir6.2 subunit of the adenosine triphosphate (ATP)-sensitive potassium (K
ATP ) channel, may serve as a molecular gatekeeper for Kir6.2/SUR1 channels and leads to the development of neonatal diabetes when mutated. A small reduction in ATP inhibition in the heterozygous state and a rise in the whole-cell KATP current is said to be attributable to this mutation. It tackles two positions being adopted by the tryptophan residue that corresponds to W68.- Published
- 2011
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38. Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children.
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Hameed, Shihab, Ellard, Sian, Woodhead, Helen J., Neville, Kristen A., Walker, Jan L., Craig, Maria E., Armstrong, Taylor, Liping Yu, Eisenbarth, George S., Hattersley, Andrew T., and Verge, Charles F.
- Subjects
DIAGNOSIS of diabetes ,TYPE 2 diabetes diagnosis ,AUTOANTIBODIES ,C-peptide ,COMPUTER software ,DIABETES ,DIFFERENTIAL diagnosis ,ENZYME-linked immunosorbent assay ,GENES ,GENETIC mutation ,STATISTICAL sampling ,DATA analysis - Abstract
Hameed S, Ellard S, Woodhead HJ, Neville KA, Walker JL, Craig ME, Armstrong T, Yu L, Eisenbarth GS, Hattersley AT, Verge CF. Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children. Background: Autoantibody-negative children diagnosed with type 1 diabetes might have unrecognized monogenic or type 2 diabetes. Research design and methods: At diagnosis of type 1 diabetes (between ages 0.5 and 16.3 yr, n = 470), autoantibodies [glutamic acid decarboxylase (GAD), insulinoma-associated protein 2 (IA2), insulin autoantibodies (IAA), and/or islet cell antibody (ICA)] were positive (ab+) in 330 and negative in 37 (unknown in 103). Autoantibody-negative patients were retested at median diabetes duration of 3.2 yr (range 0.9−16.2) for autoantibodies (GAD, IA2, ZnT8), human leukocyte antigen (HLA) typing, non-fasting C-peptide, and sequencing of HNF4A, HNF1A, KCNJ11, and INS. Results: Nineteen (5% of 367) remained persistently autoantibody negative (PAN), 17 were positive on repeat testing (PORT), and 1 refused retesting. No mutations were found in PORT. One PAN was heterozygous for P112L mutation in HNF1A and transferred from insulin to oral gliclazide. Another PAN transferred to metformin and the diagnosis was revised to type 2 diabetes. The remaining 17 PAN were indistinguishable from the ab+ group by clinical characteristics. HLA genotype was at high risk for type 1 diabetes in 82% of remaining PAN and 100% of PORT. After excluding patients with diabetes duration <1 yr, C-peptide was detectable more frequently in the remaining PAN (7/16) and PORT (6/17) than in a random selection of ab+ (3/28, p = 0.03). Conclusions: The diagnosis of type 1 diabetes should be reevaluated in PAN patients, because a subset has monogenic or type 2 diabetes. The remaining PAN have relatively preserved C-peptide compared with ab+, suggesting slower β-cell destruction, but a very high frequency of diabetogenic HLA, implying that type 1B (idiopathic) diabetes is rare. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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39. Polygenic Risk Variants for Type 2 Diabetes Susceptibility Modify Age at Diagnosis in Monogenic HNF1A Diabetes.
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Allen, Hana Lango, Johansson, Stefan, Ellard, Sian, Shields, Beverley, Hertel, Jens K., Ræder, Helge, Colclough, Kevin, Molven, Anders, Frayling, Timothy M., Njølstad, Pål R., Hattersley, Andrew T., and Weedon, Michael N.
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TYPE 2 diabetes ,GENETIC mutation ,HYPERGLYCEMIA ,NUCLEOTIDES ,MONOGENIC & polygenic inheritance (Genetics) ,DIABETES - Abstract
OBJECTIVE--Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis. RESEARCH DESIGN AND METHODS--Fifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient. RESULTS--We confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1 years if present, P = 1.6 x 10
10 ) and HNF1A mutation position (-5.2 years if at least two isoforms affected, P = 1.8 x 10-2 ). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 x 10-4 ) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 x 10-38 ). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 x 10-3 ). CONCLUSIONS--We show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants. Diabetes 59:266-271, 2010 [ABSTRACT FROM AUTHOR]- Published
- 2010
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40. Mutations in the ABCC8 (SUR1 subunit of the KATP channel) gene are associated with a variable clinical phenotype.
- Author
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Klupa, Tomasz, Kowalska, Irina, Wyka, Krystyna, Skupien, Jan, Patch, Ann-Marie, Flanagan, Sarah E., Noczynska, Anna, Arciszewska, Malgorzata, Ellard, Sian, Hattersley, Andrew T., Sieradzki, Jacek, Mlynarski, Wojciech, and Malecki, Maciej T.
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GENETIC mutation ,DIABETES ,INSULIN ,INSULIN shock ,HETEROZYGOSITY - Abstract
Objective Mutations in the ABCC8 gene encoding the SUR1 subunits of the β-cell K-ATP channel cause neonatal diabetes (ND) mellitus. We aimed to determine the contribution of ABCC8 gene to ND in Poland, to describe the clinical phenotype associated with its mutations and to examine potential modifying factors. Patients The Nationwide Registry of ND in Poland includes patients diagnosed before 6 months of age. In total 16 Kir6·2 negative patients with ND, 14 permanent and 2 relapsed transient, were examined. Measurements ABCC8 gene mutations were detected by direct sequencing. Mutation carriers’ characteristics included clinical data and biochemical parameters. In addition, we performed the hyperinsulinaemic euglycaemic clamp and tested for islet-specific antibodies in diabetic subjects. Results We identified two probands with permanent ND (one heterozygous F132V mutation carrier and one compound heterozygote with N23H and R826W mutations) and two others with relapsed transient ND (heterozygotes for R826W and V86A substitutions, respectively). One subject, a heterozygous relative with the R826W mutation, had adult onset diabetes. There were striking differences in the clinical picture of the mutation carriers as the carrier of two mutations, N23H and R826W, was controlled on diet alone with HbA
1c of 7·3%, whereas the F132V mutation carrier was on 0·66 IU/kg/day of insulin with HbA1c of 11·7%. The C-peptide level varied from 0·1 ng/ml (F132V) to 0·75 ng/ml (V86A). We also observed a variable insulin resistance, from moderate ( M = 5·5 and 5·6 mg/kg/min, respectively, in the two R826W mutation carriers) to severe ( M = 2·6 mg/kg/min in the F132V mutation carrier). We were able to transfer two patients off insulin to sulphonylurea (SU) and to reduce insulin dose in one other patient. Interestingly, there was no response to SU in the most insulin resistant F132V mutation carrier despite high dose of glibenclamide. All examined auto-antibodies were present in one of the subjects, the V86A mutation carrier, although this did not seem to influence the clinical picture, as we were able to transfer this girl off insulin. Conclusion Mutations in SUR1 are the cause of about 15% of Kir6·2 negative permanent ND in Poland. The clinical phenotype of SUR1 diabetic mutation carriers is heterogeneous and it appears to be modified by variable sensitivity to insulin. [ABSTRACT FROM AUTHOR]- Published
- 2009
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41. Low Frequency Variants in the Exons Only Encoding Isoform A of HNF1A Do Not Contribute to Susceptibility to Type 2 Diabetes.
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Jafar-Mohammadi, Bahram, Groves, Christopher J., Owen, Katharine R., Frayling, Timothy M., Hattersley, Andrew T., McCarthy, Mark I., and Gloyn, Anna L.
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TYPE 2 diabetes ,DIABETES complications ,GENETICS of diabetes ,EXONS (Genetics) ,GENETIC mutation ,ETIOLOGY of diseases ,GENETIC polymorphisms ,PEOPLE with diabetes ,GENETIC testing - 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 lowfrequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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42. Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes.
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Rubio-Cabezas, Oscar, Minton, Jayne A.L., Caswell, Richard, Shield, Julian P., Deiss, Dorothee, Sumnik, Zdenek, Cayssials, Amely, Herr, Mathias, Loew, Anja, Lewis, Vaughan, Ellard, Sian, and Hattersley, Andrew T.
- Subjects
GENETIC mutation ,DIABETES ,NEONATAL diseases ,IMMUNOLOGIC diseases ,HYPOTHYROIDISM ,NEPHROTIC syndrome - Abstract
OBJECTIVE-- Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM). RESEARCH DESIGN AND METHODS-- The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes. RESULTS -- We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes (P = 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n = 2) or nephrotic syndrome (n = 1) and survival to 12-15 years. CONCLUSIONS-- FOXP3 mutations result in ∼4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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43. The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development.
- Author
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Harries, Lorna W., Locke, Jonathan M., Shields, Beverley, Hanley, Neil A., Hanley, Karen Piper, Steele, Anna, Njølstad, Pål R., Ellard, Sian, and Hattersley, Andrew T.
- Subjects
GENETICS of diabetes ,GENETIC mutation ,EXONS (Genetics) ,PROMOTERS (Genetics) ,FETAL development - Abstract
OBJECTIVE--Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype. RESEARCH DESIGN AND METHODS--We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations. RESULTS--HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4-6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P = 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P < 0.00001). CONCLUSIONS--We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene. Diabetes 57:1745-1752, 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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44. Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations.
- Author
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Kapoor, Ritika R., Locke, Jonathan, Colclough, Kevin, Wales, Jerry, Conn, Jennifer J., Hattersley, Andrew T., Ellard, Sian, and Hussain, Khalid
- Subjects
HYPOGLYCEMIA ,INSULIN ,DIABETES ,GENETIC mutation ,LIVER cells ,PANCREATIC beta cells ,TRANSCRIPTION factors - Abstract
OBJECTIVE--Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor (HNF)-4α are known to cause maturity-onset diabetes of the young (MODY), which is characterized by autosomal-dominant inheritance and impaired glucose-stimulated insulin secretion from pancreatic β-cells. HNF-4α has a key role in regulating the multiple transcriptional factor networks in the islet. Recently, heterozygous mutations in the HNF4A gene were reported to cause transient hyperinsulinemic hypoglycemia associated with macrosomia. RESEARCH DESIGN AND METHODS--Three infants presented with macrosomia and severe hypoglycemia with a positive family history of MODY. The hypoglycemia was confirmed to be due to hyperinsulinism, and all three patients required diazoxide therapy to maintain normoglycemia. Two of the three infants are still requiring diazoxide therapy at 8 and 18 months, whereas one of them had resolution of hyperinsulinemic hypoglycemia at 32 months of age. RESULTS--Sequencing of the HNF4A gene identified heterozygous mutations in all three families. In family 1, a frameshift mutation L330fsdel17ins9 (c.987 1003del17ins9; p.Leu330fs) was present in the proband; a mutation affecting the conserved A nucleotide of the intron 2 branch site (c.264-21A>G) was identified in the proband of family 2; and finally a nonsense mutation, Y16X (c.48C>G, p.Tyr16X), was found in the proband of family 3. CONCLUSIONS--Heterozygous HNF4A mutations can therefore cause both transient and persistent hyperinsulinemic hypoglycemia associated with macrosomia. We recommend that macrosomic infants with transient or persistent hyperinsulinemic hypoglycemia should be screened for HNF4A mutations if there is a family history of youth-onset diabetes. Diabetes 57: 1659-1663, 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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45. Insulin Mutation Screening in 1,044 Patients With Diabetes.
- Author
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Edghill, Emma L., Flanagan, Sarah E., Patch, Ann-Marie, Boustred, Chris, Parrish, Andrew, Shields, Beverley, Shepherd, Maggie H., Hussain, Khalid, Kapoor, Ritika R., Malecki, Maciej, MacDonald, Michael J., Støy, Julie, Steiner, Donald F., Philipson, Louis H., Bell, Graeme I., Hattersley, Andrew T., and Ellard, Sian
- Subjects
GENETIC mutation ,INSULIN ,DIABETES ,GENES ,NEWBORN infants - Abstract
OBJECTIVE--Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood. RESEARCH DESIGN AND METHODS--The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes. RESULTS--We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K
+ channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant. CONCLUSIONS--We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age. [ABSTRACT FROM AUTHOR]- Published
- 2008
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46. Mutations in the Glucokinase Gene of the Fetus Result in Reduced Placental Weight.
- Author
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Shields, Beverley M., Spyer, Gill, Slingerland, Annabelle S., Knight, Bridget A., Ellard, Sian, Clark, Penelope M., Hauguel-de Mouzon, Sylvie, and Hattersley, Andrew T.
- Subjects
GENETIC mutation ,GENES ,GLUCOKINASE ,FETUS ,PLACENTA - Abstract
OBJECTIVE -- In human pregnancy, placental weight is strongly associated with birth weight. It is uncertain whether there is regulation of the placenta by the fetus or vice versa. We aimed to test the hypothesis that placental growth is mediated, either directly or indirectly, by fetal insulin. RESEARCH DESIGN AND METHODS -- Birth weight and placental weight were measured in 4-3 offspring of 21 parents with mutations in the glucokinase (GCK) gene (25 had inherited the mutation and 18 had not), which results in reduced fetal insulin secretion. Birth weight, placental weight, umbilical cord insulin, and maternal glucose and insulin concentrations were measured in 573 nondiabetic, healthy, term pregnancies. RESULTS -- GCK mutation carriers were lighter and also had smaller placentas (610 vs. 720 g, P = 0.042). This difference was also seen in 17 discordant sibling pairs (600 vs. 720 g, P = 0.003). GCK mRNA was not detected in the placenta by RT-PCR. In the normal pregnancies, placental weight was strongly correlated with birth weight (r = 0.61, P < 0.001). Cord insulin concentrations were directly related to placental weight (r = 0.28) and birth weight (r = 0.36) (P < 0.001 for both). CONCLUSIONS -- These results suggest that insulin, directly or indirectly, plays a role in placental growth, especially as a mutation in the GCK gene, which is known to only alter fetal insulin secretion, results in altered placental weight. This finding is consistent with the preferential localization of the insulin receptors in the fetal endothelium of the placenta in the last trimester of pregnancy. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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47. Effective Treatment With Oral Sulfonylureas in Patients With Diabetes Due to Sulfonylurea Receptor 1 (SUR1) Mutations.
- Author
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Rafiq, Meena, Flanagan, Sarah E., Patch, Ann-Marie, Shields, Beverley M., Ellard, Sian, and Hattersley, Andrew T.
- Subjects
SULFONYLUREAS ,PEOPLE with diabetes ,GENETIC mutation ,DRUG efficacy ,DIABETES - Abstract
OBJECTIVE -- Neonatal diabetes can result from mutations in the Kir6.2 or sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K
+ 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 = 0.01). When compared with Kir6.2 patients, SUR1 patients needed lower doses of both insulin before transfer (0.4 vs. 0.7 units ⋅ kg-1 ⋅ day-1 ; P = 0.002) and sulfonylureas after transfer (0.26 vs. 0.45 mg ⋅ kg-1 ⋅ day-1 ; P = 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. [ABSTRACT FROM AUTHOR]- Published
- 2008
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48. Mutations in ATP-Sensitive K[sup +] Channel Genes Cause Transient Neonatal Diabetes and Permanent Diabetes in Childhood or Adulthood.
- Author
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Flanagan, Sarah E., Patch, Ann-Marie, Mackay, Deborah J. G., Edghill, Emma L., Gloyn, Anna L., Robinson, David, Shield, Julian P. H., Temple, Karen, Ellard, Sian, and Hattersley, Andrew T.
- Subjects
DIABETES ,NEONATAL diseases ,DIABETES in children ,POTASSIUM channels ,GENETIC mutation ,PANCREATIC beta cells ,PEOPLE with diabetes ,SULFONYLUREAS - Abstract
Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of fife, with remission in infancy or early childhood. For ∼50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K
+ channel (KATP channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic β-cell K[sub ATP] channel, were sequenced. KATP channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted earlier (all P < 0.001). K[sub ATP] channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). KATP channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes. Diabetes 56:1930-1937, 2007 [ABSTRACT FROM AUTHOR]- Published
- 2007
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49. Contrasting Insulin Sensitivity of Endogenous Glucose Production Rate in Subjects With Hepatocyte Nuclear Factor-1β and -1α Mutations.
- Author
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Brackenridge, Anna, Pearson, Ewan R., Shojaee-Moradie, Fariba, Hattersley, Andrew T., Russell-Jones, David, and Umpleby, A. Margot
- Subjects
TRANSCRIPTION factors ,LIVER cells ,DIABETES ,GENETIC mutation ,INSULIN - Abstract
Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1α and -1β result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1α and -1β, HNF-β mutation carriers have hyperinsulinemia, whereas HNF-1α mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1β mutation carriers are insulin resistant. The endogenous glucose production rate and rate of glucose uptake were measured with a two-step, low-dose (0.3 mU ⋅ kg
-1 ⋅ min-1 ) and high-dose (1.5 mU ⋅ kg-1 ⋅ min-1 ) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-²H2 ]glucose, in six subjects with HNF-1α mutations, six subjects with HNF-1β mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1β subjects but was suppressed by 89% in HNF-1α subjects (P = 0.004) and 80% in control subjects (P < 0.001). Insulin-stimulated glucose uptake and suppression of lipolysis were similar in all groups at low- and high-dose insulin. Subjects with HNF-1β mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1α in the liver and possibly the kidney. This may be mediated through regulation by HNF-1β of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK. Diabetes 55:405-411, 2006 [ABSTRACT FROM AUTHOR]- Published
- 2006
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50. A Large-Scale Association Analysis of Common Variation of the HNF1α Gene With Type 2 Diabetes in the U.K. Caucasian Population.
- Author
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Weedon, Michael N., Owen, Katharine R., Shields, Beverley, Hitman, Graham, Walker, Mark, McCarthy, Mark I., Hattersley, Andrew T., and Frayling, Timothy M.
- Subjects
TYPE 2 diabetes ,TRANSCRIPTION factors ,PANCREATIC beta cells ,GENETIC mutation ,GENETICS - Abstract
HNF1α (TCF1) is a key transcription factor that is essential for pancreatic β-cell development and function. Rare mutations of HNF1α cause maturity-onset diabetes of the young. A common variant, G319S, private to the Oji-Cree population, predisposes to type 2 diabetes, but the role of common HNF1α variation in European populations has not been comprehensively assessed. We determined the linkage disequilibrium and haplotype structure across the HNF1α gene region using 29 single nucleotide polymorphisms (SNPs). Eight tagging SNPs (tSNPs) that efficiently capture common haplotypes and the amino acid-changing variant, A98V, were genotyped in 5,307 subjects (2,010 type 2 diabetic case subjects, 1,643 control subjects, and 1,654 members of 521 families). We did not find any evidence of association between the tSNPs or haplotypes and type 2 diabetes. We could exclude odds ratios (ORs) > 1.25 for all tSNPs. The rare V98 allele (∼3% frequency) showed possible evidence of association with type 2 diabetes (OR 1.23 [95% CI 0.99-1.54], P = 0.07), a result that was supported by meta-analysis of this and published studies (OR 1.31 [1.08-1.59], P = 0.007). Further studies are required to investigate this association, demonstrating the difficulty of defining the role of rare (<5%) alleles in type 2 diabetes risk. Diabetes 54:2487-2491, 2005 [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
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