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Deborah J.g. Mackay - One of the best experts on this subject based on the ideXlab platform.
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Clinical utility gene card for: Transient Neonatal Diabetes Mellitus, 6q24-related
European Journal of Human Genetics, 2014Co-Authors: Deborah J.g. Mackay, Guiomar Perez De Nanclares, Reiner Siebert, Susanne Bens, I. Karen TempleAbstract:aOwing to very small patient numbers, the precise percentages of different molecular aetiologies differ slightly as the sizes of patient cohorts increase. b490% of paternal uniparental disomy in 6q24 TNDM is whole-chromosome isodisomy; however, segmental UPD and heterodisomy are also seen. Maternal uniparental disomy of chromosome 6 is not associated with 6q24 TNDM. cPaternally inherited duplications of varying sizes have been identified in 6q24 TNDM, but as all contain PLAGL1, they are here designated PLAGL1 duplications. Maternally inherited duplications of PLAGL1 are not associated with 6q24 TNDM. d60% of cases with PLAGL1 hypomethylation have Multilocus Methylation Defect, that is, defects in imprinted DNA methylation at multiple imprinted loci (MLMD). Of these, approximately half have homozygous mutation of ZFP573 (a mutation database exists for ZFP57: www.lovd.nl/ ZFP57). PLAGL1 hypomethylation may also be part of MLMD associated with rare mutations in NLRP2 (NM_001174081), NLRP7 (NM_001127255) and KHDC3L (NM_001017361), but individuals affected by such syndromes may not present with 6q24 TNDM.
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no evidence for pathogenic variants or maternal effect of zfp57 as the cause of beckwith wiedemann syndrome
European Journal of Human Genetics, 2012Co-Authors: Susanne E Boonen, Deborah J.g. Mackay, Johanne M D Hahnemann, Niels Tommerup, Zeynep Tümer, Karen Brondumnielsen, Karen GrønskovAbstract:Beckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome, which, in 50–60% of sporadic cases, is caused by hypomethylation of KCNQ1OT1 differentially methylated region (DMR) at chromosome 11p15.5. The underlying defect of this hypomethylation is largely unknown. Recently, recessive mutations of the ZFP57 gene were reported in patients with transient Neonatal Diabetes Mellitus type 1, showing hypomethylation at multiple imprinted loci, including KCNQ1OT1 DMR in some. The aim of our study was to determine whether ZFP57 alterations were a genetic cause of the hypomethylation at KCNQ1OT1 DMR in patients with BWS. We sequenced ZFP57 in 27 BWS probands and in 23 available mothers to test for a maternal effect. We identified three novel, presumably benign sequence variants in ZFP57; thus, we found no evidence for ZFP57 alterations as a major cause in sporadic BWS cases.
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Transient Neonatal Diabetes Mellitus type 1
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2010Co-Authors: Deborah J.g. Mackay, I. Karen TempleAbstract:Transient Neonatal Diabetes Mellitus type 1 (TNDM1) is a rare but remarkable form of Diabetes which presents in infancy, resolves in the first months of life, but then frequently recurs in later life. It is caused by overexpression of the imprinted genes PLAGL1 and HYMAI on human chromosome 6q24. The expression of these genes is normally restricted to the paternal allele as a result of maternal DNA methylation. TNDM1 is not associated with mutation of PLAGL1 or HYMAI, but rather with their overexpression via uniparental disomy, chromosome duplication, or relaxation of imprinting. Study of patients with TNDM1 has provided valuable insights into the causes of imprinting disorders. Over half of patients with maternal hypomethylation at the TNDM1 locus have additional hypomethylation of other maternally methylated imprinted genes throughout the genome, and the majority of these patients have mutations in the transcription factor ZFP57. TNDM1 with maternal hypomethylation has also been observed in patients conceived by assisted reproduction, and in discordant monozygotic twins. The variable clinical features of TNDM1 may be associated with variation in the nature of the underlying epigenetic and genetic mutations, and future study of this disorder is likely to yield further insights not only into the biological mechanisms of imprinting, but also into the contribution of epigenetics to Diabetes.
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assessment of the role of common genetic variation in the transient Neonatal Diabetes Mellitus tndm region in type 2 Diabetes a comparative genomic and tagging single nucleotide polymorphism approach
Diabetes, 2006Co-Authors: Anna L Gloyn, Deborah J.g. Mackay, Andrew T Hattersley, Michael N Weedon, Mark I Mccarthy, Mark Walker, G A Hitman, Bridget A Knight, Katharine R Owen, Timothy M FraylingAbstract:Recent evidence supports the strong overlap between genes implicated in monogenic Diabetes and susceptibility to type 2 Diabetes. Transient Neonatal Diabetes Mellitus (TNDM) is a rare disorder associated with overexpression of genes at a paternally expressed imprinted locus on chromosome 6q24. There are two overlapping genes in this region: the transcription factor zinc finger protein associated with cell cycle control and apoptosis ( ZAC also known as PLAGL1 ) and HYMA1 , which encodes an untranslated mRNA. Several type 2 Diabetes linkage studies have reported linkage to chromosome 6q22–25. We hypothesized that common genetic variation at this TNDM region influences type 2 Diabetes susceptibility. In addition to the coding regions, we used comparative genomic analysis to identify conserved noncoding regions, which were resequenced for single nucleotide polymorphism (SNP) discovery in 47 individuals. Twenty-six SNPs were identified. Fifteen tag SNPs (tSNPs) were successfully genotyped in a large case-control ( n = 3,594) and family-based ( n = 1,654) study. We did not find any evidence of association or overtransmission of any tSNP to affected offspring or of a parent-of-origin effect. Using a study sufficiently powered to detect odds ratios of
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a maternal hypomethylation syndrome presenting as transient Neonatal Diabetes Mellitus
Human Genetics, 2006Co-Authors: Deborah J.g. Mackay, Susanne E Boonen, Johanne M D Hahnemann, Pal R Njolstad, Jill Claytonsmith, Judith A Goodship, Sarina G Kant, Nathaniel H RobinAbstract:The expression of imprinted genes is mediated by allele-specific epigenetic modification of genomic DNA and chromatin, including parent of origin-specific DNA methylation. Dysregulation of these genes causes a range of disorders affecting pre- and post-natal growth and neurological function. We investigated a cohort of 12 patients with transient Neonatal Diabetes whose disease was caused by loss of maternal methylation at the TNDM locus. We found that six of these patients showed a spectrum of methylation loss, mosaic with respect to the extent of the methylation loss, the tissues affected and the genetic loci involved. Five maternally methylated loci were affected, while one maternally methylated and two paternally methylated loci were spared. These patients had higher birth weight and were more phenotypically diverse than other TNDM patients with different aetiologies, presumably reflecting the influence of dysregulation of multiple imprinted genes. We propose the existence of a maternal hypomethylation syndrome, and therefore suggest that any patient with methylation loss at one maternally-methylated locus may also manifest methylation loss at other loci, potentially complicating or even confounding the clinical presentation.
Andrew T Hattersley - One of the best experts on this subject based on the ideXlab platform.
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pancreas and gallbladder agenesis in a newborn with semilobar holoprosencephaly a case report
BMC Medical Genetics, 2017Co-Authors: Robert Hilbrands, Andrew T Hattersley, Kathelijn Keymolen, Alex Michotte, Miriam Marichal, Filip Cools, Anieta Goossens, Peter Int Veld, Jean De Schepper, Harry HeimbergAbstract:Pancreatic agenesis is an extremely rare cause of Neonatal Diabetes Mellitus and has enabled the discovery of several key transcription factors essential for normal pancreas and beta cell development. We report a case of a Caucasian female with complete pancreatic agenesis occurring together with semilobar holoprosencephaly (HPE), a more common brain developmental disorder. Clinical findings were later confirmed by autopsy, which also identified agenesis of the gallbladder. Although the sequences of a selected set of genes related to pancreas agenesis or HPE were wild-type, the patient’s phenotype suggests a genetic defect that emerges early in embryonic development of brain, gallbladder and pancreas. Developmental defects of the pancreas and brain can occur together. Identifying the genetic defect may identify a novel key regulator in beta cell development.
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AB131. Genotype, phenotype of transient Neonatal Diabetes Mellitus
Annals of Translational Medicine, 2015Co-Authors: Ngoc Thi Bich Can, Andrew T Hattersley, Thao Phuong Bui, Khanh Ngoc Nguyen, Dat Phu Nguyen, Maria E. Craig, Hoan Thi NguyễnAbstract:Background and objective Transient Neonatal Diabetes Mellitus (TNDM) is a rare but remarkable form of Diabetes which presents in infancy, resolves in the first months of life, but then frequently recurs in later life. It is caused by overexpression of the imprinted genes PLAGL1 and HYMAI on human chromosome 6q24, ABCC8 or KCNJ11 mutation. Over half of patients with maternal hypomethylation at the TNDM1 locus have additional hypomethylation of other maternally methylated imprinted genes throughout the genome, and the majority of these patients havemutations in the transcription factor ZFP57. This article aims to describe clinical features and laboratory manifestations of patient with TNDM and evaluate outcome of management.
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clinical presentation of 6q24 transient Neonatal Diabetes Mellitus 6q24 tndm and genotype phenotype correlation in an international cohort of patients
Diabetologia, 2013Co-Authors: Sian Ellard, Sarah E Flanagan, Louise E Docherty, S Kabwama, A Lehmann, E Hawke, L Harrison, Andrew T HattersleyAbstract:Aims/hypothesis 6q24 transient Neonatal Diabetes Mellitus (TNDM) is a rare form of Diabetes presenting in the Neonatal period that remits during infancy but, in a proportion of cases, recurs in later life. We aim to describe the clinical presentation of 6q24 TNDM in the largest worldwide cohort of patients with defined molecular aetiology, in particular seeking differences in presentation or clinical history between aetiological groups. Methods One-hundred and sixty-three patients with positively diagnosed 6q24 TNDM were ascertained from Europe, the Americas, Asia and Australia. Clinical data from referrals were recorded and stratified by the molecular aetiology of patients. Results 6q24 TNDM patients presented at a modal age of one day, with growth retardation and hyperglycaemia, irrespective of molecular aetiology. There was a positive correlation between age of presentation and gestational age, and a negative correlation between adjusted birthweight SD and age of remission. Congenital anomalies were significantly more frequent in patients with paternal uniparental disomy of chromosome 6 or hypomethylation of multiple imprinted loci defects than in those with 6q24 duplication or isolated hypomethylation defects. Patients with hypomethylation had an excess representation of assisted conception at 15%. Conclusions/interpretation This, the largest case series of 6q24 TNDM published, refines and extends the clinical phenotype of the disorder and confirms its clinical divergence from other monogenic TNDM in addition to identifying previously unreported clinical differences between 6q24 subgroups.
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clinical presentation of 6q24 transient Neonatal Diabetes Mellitus 6q24 tndm and genotype phenotype correlation in an international cohort of patients
Diabetologia, 2013Co-Authors: Louise E Docherty, Sian Ellard, Sarah E Flanagan, Andrew T Hattersley, S Kabwama, A Lehmann, E Hawke, L Harrison, Julian P H ShieldAbstract:6q24 transient Neonatal Diabetes Mellitus (TNDM) is a rare form of Diabetes presenting in the Neonatal period that remits during infancy but, in a proportion of cases, recurs in later life. We aim to describe the clinical presentation of 6q24 TNDM in the largest worldwide cohort of patients with defined molecular aetiology, in particular seeking differences in presentation or clinical history between aetiological groups. One-hundred and sixty-three patients with positively diagnosed 6q24 TNDM were ascertained from Europe, the Americas, Asia and Australia. Clinical data from referrals were recorded and stratified by the molecular aetiology of patients. 6q24 TNDM patients presented at a modal age of one day, with growth retardation and hyperglycaemia, irrespective of molecular aetiology. There was a positive correlation between age of presentation and gestational age, and a negative correlation between adjusted birthweight SD and age of remission. Congenital anomalies were significantly more frequent in patients with paternal uniparental disomy of chromosome 6 or hypomethylation of multiple imprinted loci defects than in those with 6q24 duplication or isolated hypomethylation defects. Patients with hypomethylation had an excess representation of assisted conception at 15%. This, the largest case series of 6q24 TNDM published, refines and extends the clinical phenotype of the disorder and confirms its clinical divergence from other monogenic TNDM in addition to identifying previously unreported clinical differences between 6q24 subgroups.
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permanent Neonatal Diabetes Mellitus prevalence and genetic diagnosis in the search for Diabetes in youth study
Pediatric Diabetes, 2012Co-Authors: Roopa Kanakatti Shankar, Catherine Pihoker, Lawrence M Dolan, Debra Standiford, Angela Badaru, Dana Dabelea, Beatriz L Rodriguez, Mary Helen Black, Giuseppina Imperatore, Andrew T HattersleyAbstract:Background Neonatal Diabetes Mellitus (NDM) is defined as Diabetes with onset before 6 months of age. Nearly half of individuals with NDM are affected by permanent Neonatal Diabetes Mellitus (PNDM). Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of PNDM. Objective To estimate the prevalence of PNDM among SEARCH for Diabetes in Youth (SEARCH) study participants (2001–2008) and to identify the genetic mutations causing PNDM. Methods SEARCH is a multicenter population-based study of Diabetes in youth <20 yr of age. Participants diagnosed with Diabetes before 6 months of age were invited for genetic testing for mutations in the KCNJ11, ABCC8, and INS genes. Results Of the 15,829 SEARCH participants with Diabetes, 39 were diagnosed before 6 months of age. Thirty-five of them had PNDM (0.22% of all Diabetes cases in SEARCH), 3 had transient Neonatal Diabetes that had remitted by 18 months and 1 was unknown. The majority of them (66.7%) had a clinical diagnosis of type1 Diabetes by their health care provider. Population prevalence of PNDM in youth <20 yr was estimated at 1 in 252 000. Seven participants underwent genetic testing; mutations causing PNDM were identified in five (71%), (two KCNJ11, three INS). Conclusions We report the first population-based frequency of PNDM in the US based on the frequency of PNDM in SEARCH. Patients with NDM are often misclassified as having type1 Diabetes. Widespread education is essential to encourage appropriate genetic testing and treatment of NDM.
Sian Ellard - One of the best experts on this subject based on the ideXlab platform.
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permanent Neonatal Diabetes Mellitus and neurological abnormalities due to a novel homozygous missense mutation in neurod1
Pediatric Diabetes, 2018Co-Authors: Huseyin Demirbilek, Sian Ellard, Sarah E Flanagan, Elisa De Franco, Nihal Hatipoglu, Ulku Gul, Zeynep Uzan Tatli, Selim KurtogluAbstract:S. E. F. has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number: 105636/Z/14/Z). S. E. is a Wellcome Trust Senior Investigator.
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clinical and molecular characterization of children with Neonatal Diabetes Mellitus at a tertiary care center in northern india
Indian Pediatrics, 2017Co-Authors: Vandana Jain, Venkatesan Radha, Viswanathan Mohan, Amit Kumar Satapathy, Jaivinder Yadav, Rajni Sharma, Elisa De Franco, Sian EllardAbstract:To study the genetic mutations and clinical profile in children with Neonatal Diabetes Mellitus Genetic evaluation, clinical management and follow-up of infants with Neonatal Diabetes Eleven infants were studied of which eight had permanent Neonatal Diabetes. Median age at presentation was 8 weeks and mean (SD) birth weight was 2.4 (0.5) kg. Pathogenic genetic mutations were identified in 7 (63.6%) children; 3 infants with mutations in KCNJ11 gene and 1 in ABCC8 were switched to oral sulfonylureas; 2 infants had mutations in INS and 1 in ZFP57. Neonatal Diabetes Mellitus is a heterogeneous disorder. Identification of genetic cause guides clinical management.
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case report maternal mosaicism resulting in inheritance of a novel gata6 mutation causing pancreatic agenesis and Neonatal Diabetes Mellitus
Diagnostic Pathology, 2017Co-Authors: Daphne Yau, Sian Ellard, Sarah E Flanagan, Elisa De Franco, Miriam Blumenkrantz, John J MitchellAbstract:Background Haploinsufficiency of the GATA6 transcription factor gene was recently found to be the most common cause of pancreatic agenesis, a rare cause of Neonatal Diabetes Mellitus. Although most cases are de novo, we describe three siblings with inherited GATA6 haploinsufficiency and the rare finding of parental mosaicism.
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case report maternal mosaicism resulting in inheritance of a novel gata6 mutation causing pancreatic agenesis and Neonatal Diabetes Mellitus
Diagnostic Pathology, 2017Co-Authors: Daphne Yau, Sian Ellard, Sarah E Flanagan, Elisa De Franco, Miriam Blumenkrantz, John J MitchellAbstract:Haploinsufficiency of the GATA6 transcription factor gene was recently found to be the most common cause of pancreatic agenesis, a rare cause of Neonatal Diabetes Mellitus. Although most cases are de novo, we describe three siblings with inherited GATA6 haploinsufficiency and the rare finding of parental mosaicism. The proband was born at term with severe intrauterine growth restriction, the first child of non-consanguineous parents. Diabetes occurred on day of life 1 with pancreatic exocrine insufficiency noted at several months of age. Pancreatic agenesis with absent gallbladder was confirmed when he underwent congenital diaphragmatic hernia and intestinal malrotation repair. A patent ductus arteriosus and pulmonary stenosis were repaired in infancy. Neurocognitive development has been normal. A second pregnancy was terminated due to tetralogy of Fallot and pulmonary hypoplasia secondary to congenital diaphragmatic hernia. The fetus also demonstrated severe pancreatic hypoplasia, gallbladder agenesis and intestinal rotation abnormalities. Despite severe hypoplasia, the pancreas demonstrated normal islet histology. Another sibling was found to have multiple cardiac abnormalities, requiring procedural intervention. Given the proband’s spectrum of congenital anomalies, Sanger sequencing of the GATA6 gene was performed, revealing a novel heterozygous c.635_660del frameshift mutation (p.Pro212fs). The mutation is predicted to be pathogenic, resulting in inclusion of a premature stop codon and likely degradation of the gene transcript by nonsense-mediated decay. The abortus and the sibling with the cardiac defect were both found to have the mutation, while the father and remaining sibling were negative. The mother, who is healthy with no evidence of Diabetes or cardiac disease, is mosaic for the mutation at a level of 11% in her peripheral leukocytes by next-generation sequencing. We highlight a rare mechanism of pancreatic agenesis, this being only the second report of parental mosaicism for a GATA6 mutation and one of a handful of inherited cases. We also further define the phenotypic variability of GATA6 haploinsufficiency, even in individuals carrying the same mutation. Mutations in GATA6 should be strongly considered in cases of Diabetes due to pancreatic hypoplasia or agenesis, and potentially affected family members should be tested regardless of phenotype.
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clinical presentation of 6q24 transient Neonatal Diabetes Mellitus 6q24 tndm and genotype phenotype correlation in an international cohort of patients
Diabetologia, 2013Co-Authors: Sian Ellard, Sarah E Flanagan, Louise E Docherty, S Kabwama, A Lehmann, E Hawke, L Harrison, Andrew T HattersleyAbstract:Aims/hypothesis 6q24 transient Neonatal Diabetes Mellitus (TNDM) is a rare form of Diabetes presenting in the Neonatal period that remits during infancy but, in a proportion of cases, recurs in later life. We aim to describe the clinical presentation of 6q24 TNDM in the largest worldwide cohort of patients with defined molecular aetiology, in particular seeking differences in presentation or clinical history between aetiological groups. Methods One-hundred and sixty-three patients with positively diagnosed 6q24 TNDM were ascertained from Europe, the Americas, Asia and Australia. Clinical data from referrals were recorded and stratified by the molecular aetiology of patients. Results 6q24 TNDM patients presented at a modal age of one day, with growth retardation and hyperglycaemia, irrespective of molecular aetiology. There was a positive correlation between age of presentation and gestational age, and a negative correlation between adjusted birthweight SD and age of remission. Congenital anomalies were significantly more frequent in patients with paternal uniparental disomy of chromosome 6 or hypomethylation of multiple imprinted loci defects than in those with 6q24 duplication or isolated hypomethylation defects. Patients with hypomethylation had an excess representation of assisted conception at 15%. Conclusions/interpretation This, the largest case series of 6q24 TNDM published, refines and extends the clinical phenotype of the disorder and confirms its clinical divergence from other monogenic TNDM in addition to identifying previously unreported clinical differences between 6q24 subgroups.
David O Robinson - One of the best experts on this subject based on the ideXlab platform.
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Bisulphite sequencing of the transient Neonatal Diabetes Mellitus DMR facilitates a novel diagnostic test but reveals no methylation anomalies in patients of unknown aetiology
Human Genetics, 2005Co-Authors: Deborah J.g. Mackay, Julian P H Shield, I. Karen Temple, David O RobinsonAbstract:Transient Neonatal Diabetes Mellitus (TNDM) is associated with overexpression of an imprinted locus on chromosome 6q24; this locus contains a differentially methylated region (DMR) consisting of an imprinted CpG island that normally allows expression only from the paternal allele of genes under its control. Three types of abnormality involving 6q24 are known to cause TNDM: paternal uniparental disomy of chromosome 6 (pUPD6), an isolated methylation defect of the imprinted CpG island at chromosome 6q24 and a duplication of 6q24 of paternal origin. A fourth group of patients has no identifiable anomaly of 6q24. Bisulphite sequencing of the DMR has facilitated the development of a diagnostic test for TNDM based on ratiometric methylation-specific polymerase chain reaction. We have applied this method to 45 cases of TNDM, including 12 with pUPD6, 11 with an isolated methylation mutation at 6q24, 16 with a duplication of 6q24 and six of unknown aetiology, together with 29 normal controls. All were correctly assigned. The method is therefore capable of detecting all known genetic causes of TNDM at 6q24, although pUPD6 and methylation mutation cases are not distinguished from one another. In addition, we have carried out bisulphite sequencing of the DMR to compare its methylation status between six TNDM patients with a known methylation mutation, six patients with no identifiable 6q24 mutation and six normal controls. Whereas methylation mutation patients showed a near-total absence of DNA methylation at the TNDM locus, the patients with no identified molecular anomaly showed no marked methylation variation from controls.
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relaxation of imprinted expression of zac and hymai in a patient with transient Neonatal Diabetes Mellitus
Human Genetics, 2002Co-Authors: Deborah J.g. Mackay, Julian P H Shield, I K Temple, A M Coupe, J N P Storr, David O RobinsonAbstract:Transient Neonatal Diabetes Mellitus (TNDM) is a rare disease believed to result from overexpression of a paternally expressed gene controlled by a differentially methylated CpG island on chromosome 6q24. Two genes partially overlap the island: the cell-cycle-control gene ZAC and the untranslated gene HYMAI, the function of which is currently unknown. Proof that either gene is involved in TNDM would require demonstration that imprinted expression is relaxed in TNDM patients; this has hitherto been lacking because of the rarity of the disease and the lack of imprinted expression in the lymphoblastoid cells that are generally the only resource available for study. Here, we show, for the first time, the aberrant expression of imprinted genes in a TNDM patient. In TNDM fibroblasts, the monoallelic expression of both ZAC and HYMAI is relaxed, providing strong supportive evidence that the presence of two unmethylated alleles of this locus is indeed associated with the inappropriate gene expression of neighbouring genes.
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characterization of the methylation sensitive promoter of the imprinted zac gene supports its role in transient Neonatal Diabetes Mellitus
Journal of Biological Chemistry, 2001Co-Authors: Annie Varrault, David O Robinson, Deborah J.g. Mackay, Benoit Bilanges, Eugenia Basyuk, Barbara Ahr, Celine Fernandez, Joel Bockaert, Laurent JournotAbstract:ZAC is a recently isolated zinc finger protein that induces apoptosis and cell cycle arrest. The corresponding gene is imprinted maternally through an unknown mechanism and maps to 6q24-q25, within the minimal interval harboring the gene responsible for transient Neonatal Diabetes Mellitus (TNDM) and a tumor suppressor gene involved in breast cancer. Because of its functional properties, imprinting status, and expression pattern in mammary cell lines and tumors, ZAC is the best candidate so far for both disease conditions. In the present work, we delineated ZAC genomic organization and mapped its transcriptional start site. It is noteworthy that the ZAC promoter localized to the CpG island harboring the methylation imprint associated with TNDM and methylation of this promoter silenced its activity. These data indicate that the methylation mark may have a direct effect on the silencing of the ZAC imprinted allele. Our findings further strengthen the hypothesis that ZAC is the gene responsible for TNDM and suggest a novel mechanism for ZAC inactivation in breast tumors.
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an imprinted locus associated with transient Neonatal Diabetes Mellitus
Human Molecular Genetics, 2000Co-Authors: R J Gardner, Karen I Temple, Julian P H Shield, Andrew J Mungall, Deborah J.g. Mackay, Reiner Siebert, Constantin Polychronakos, David O RobinsonAbstract:Recently, we reported the localization of a gene for transient Neonatal Diabetes Mellitus (TNDM), a rare form of childhood Diabetes, to an approximately 5.4 Mb region of chromosome 6q24. We have also shown that TNDM is associated with both paternal uniparental disomy (UPD) of chromosome 6 and paternal duplications of the critical region. The sequencing of P1-derived artificial chromosome clones from within the region of interest has allowed us to further localize the gene and to investigate the methylation status of the region. The gene is now known to reside in a 300-400 kb region of 6q24 which contains several CpG islands. At one island we have demonstrated differential DNA methylation between patients with paternal UPD of chromosome 6 and normal controls. In addition, two patients with TNDM, in whom neither paternal UPD of chromosome 6 nor duplication of 6q24 have been found, show a DNA methylation pattern identical to that of patients with paternal UPD of chromosome 6. Control individuals show a hemizygous methylation pattern. These results show that TNDM can be associated with a methylation change and identify a novel methylation imprint on chromosome 6 associated with TNDM.
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localisation of a gene for transient Neonatal Diabetes Mellitus to an 18 72 cr3000 5 4 mb interval on chromosome 6q
Journal of Medical Genetics, 1999Co-Authors: R J Gardner, John C K Barber, Julian P H Shield, Andrew J Mungall, Ian Dunham, I K Temple, David O RobinsonAbstract:Transient Neonatal Diabetes Mellitus (TNDM) is a rare condition which presents with intrauterine growth retardation, dehydration, and failure to thrive. The condition spontaneously resolves before 1 year of age but predisposes patients to type 2 Diabetes later in life. We have previously shown that, in some cases, TNDM is associated with paternal uniparental disomy (UPD) of chromosome 6 and suggested that an imprinted gene responsible for TNDM lies within a region of chromosome 6q. By analysing three families, two with duplications (family A and patient C) and one with several aVected subjects with normal karyotypes (family B), we have further defined the TNDM critical region. In patient A, polymorphic microsatellite repeat analysis identified a duplicated region of chromosome 6, flanked by markers D6S472 and D6S311. This region was identified on the Sanger Centre’s chromosome 6 radiation hybrid map (http://www.sanger.ac.uk/HGP/Chr6) and spanned approximately 60 cR3000. Using markers within the region, 418 unique P1 derived artificial chromosomes (PACs) have been isolated and used to localise the distal breakpoints of the two duplications. Linkage analysis of the familial case with a normal karyotype identified a recombination within the critical region. This recombination has been identified on the radiation hybrid map and defines the proximal end of the region of interest. We therefore propose that an imprinted gene for TNDM lies within an 18.72 cR3000 (~5.4 Mb) interval on chromosome 6q24.1-q24.3 between markers D6S1699 and D6S1010. (J Med Genet 1999;36:192‐196)
Riccardo Bonfanti - One of the best experts on this subject based on the ideXlab platform.
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differences between transient Neonatal Diabetes Mellitus subtypes can guide diagnosis and therapy
European Journal of Endocrinology, 2021Co-Authors: Riccardo Bonfanti, Ivana Rabbone, Dario Iafusco, Giacomo Diedenhofen, Carla Bizzarri, Patrizia Ippolita Patera, Petra Reinstadler, Francesco Costantino, Valeria Calcaterra, Lorenzo IughettiAbstract:Objective Transient Neonatal Diabetes Mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design Retrospective analysis of the Italian data set of patients with TNDM. Methods Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at Diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered Diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent Neonatal Diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of Diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of Diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.
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insulin therapy in Neonatal Diabetes Mellitus a review of the literature
Diabetes Research and Clinical Practice, 2017Co-Authors: Ivana Rabbone, Fabrizio Barbetti, Riccardo Bonfanti, Claudio Maffeis, R Gentilella, Gilberto Mossetto, Dario Iafusco, Elvira PiccinnoAbstract:Abstract Aims Neonatal Diabetes Mellitus (NDM) is a rare disorder, and guidance is limited regarding its optimal management. We reviewed insulin usage in NDM, with a focus on continuous subcutaneous insulin infusion (CSII). Methods A PubMed search identified 40 reports of patients with NDM treated with insulin published between 1994 and 2016. Results Data concerning treatment of NDM are limited. CSII resolves some of the issues associated with insulin therapy in neonates. No clinical trials of CSII in NDM have been reported. Case reports suggest that CSII is a safe and effective means of treating NDM. CSII was initiated to improve glycaemic control, for practicality and convenience, and to overcome difficulties associated with the maintenance of long-term intravenous catheters. CSII can provide better glycaemic control than multiple daily injections, with few hypoglycaemic events. Continuous glucose monitoring integrated with the pump helps provide more precise control of blood glucose levels. CSII generally uses short-acting insulin or rapid-acting insulin analogues, and those that are approved for use in neonates appear to be appropriate for the treatment of NDM using an insulin pump. Conclusions Information from case reports indicates that CSII is safe and effective for the management of NDM.
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successful treatment of young infants presenting Neonatal Diabetes Mellitus with continuous subcutaneous insulin infusion before genetic diagnosis
Acta Diabetologica, 2016Co-Authors: Ivana Rabbone, Fabrizio Barbetti, Marco Marigliano, Riccardo Bonfanti, Elvira Piccinno, Federica Ortolani, G Ignaccolo, Claudio Maffeis, Santino Confetto, Franco CeruttiAbstract:Neonatal Diabetes Mellitus (NDM) is defined as hyperglycemia and impaired insulin secretion with onset within 6 months of birth. While rare, NDM presents complex challenges regarding the management of glycemic control. The availability of continuous subcutaneous insulin infusion pumps (CSII) in combination with continuous glucose monitoring systems (CGM) provides an opportunity to monitor glucose levels more closely and deliver insulin more safely. We report four cases of young infants with NDM successfully treated with CSII and CGM. Moreover, in two cases with Kir 6.2 mutation, we describe the use of CSII in switching therapy from insulin to sulfonylurea treatment. Insulin pump requirement for the 4 Neonatal Diabetes cases was the same regardless of disease pathogenesis and c-peptide levels. No dilution of insulin was needed. The use of an integrated CGM system helped in a more precise control of BG levels with the possibility of several modifications of insulin basal rates. Moreover, as showed in the first two case-reports, when the treatment was switched from insulin to glibenclamide, according to identification of Kir 6.2 mutation and diagnosis of NPDM, the CSII therapy demonstrated to be helpful in allowing gradual insulin suspension and progressive introduction of sulfonylurea. During the Neonatal period, the use of CSII therapy is safe, more physiological, accurate and easier for the insulin administration management. Furthermore, CSII therapy is safe during the switch of therapy from insulin to glibenclamide for infants with permanent Neonatal Diabetes Mellitus.
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sulfonylurea treatment outweighs insulin therapy in short term metabolic control of patients with permanent Neonatal Diabetes Mellitus due to activating mutations of the kcnj11 kir6 2 gene
Diabetologia, 2006Co-Authors: Giorgio Tonini, Riccardo Bonfanti, Carla Bizzarri, M Vanelli, F Cerutti, E Faleschini, F Meschi, F Prisco, E Ciacco, Marco CappaAbstract:To the Editor, Activating missense mutations in the gene encoding potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) represent the most common cause (40 to 64%, depending on populations) of permanent Neonatal Diabetes Mellitus in patients diagnosed in the first 6 months of life [1, 2]. In addition, KCNJ11 activating mutations can lead to transient/relapsing Neonatal Diabetes [3, 4]. The KCNJ11 gene encodes the pore-forming subunit (also known as KIR6.2) of the pancreatic beta cell ATP-sensitive potassium channel (KATP), which exerts a pivotal role in glucose-regulated insulin release. In the beta cell, KIR6.2 forms a hetero-octameric complex (4:4) with the sulfonylurea receptor subtype 1 (SUR1); binding to SUR1 by sulfonylureas determines channel closure and insulin secretion [2]. In previously published cases, seven patients have been reported to respond well to the transfer from insulin to oral hypoglycaemic agents [4–8]. Here we report on the replacement of insulin with sulfonylureas in ten Italian children who have mutations in KCNJ11 (R50P, V59M [x4], K170R, R201C and R201H [x3]) and were followed in nine Diabetologia (2006) 49:2210–2213 DOI 10.1007/s00125-006-0329-x
