scholarly journals Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

2020 ◽  
Vol 4 ◽  
pp. 149
Author(s):  
Indraneel Banerjee ◽  
Senthil Senniappan ◽  
Thomas W. Laver ◽  
Richard Caswell ◽  
Martin Zenker ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Chromosome 9 ◽  
Genetic Mechanism ◽  
Targeted Sequencing ◽  
Deletion Syndrome ◽  
Recessive Mutation ◽  
Congenital Hyperinsulinism ◽  
Potential Candidate ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Chromosome 9P

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome.  A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown.  Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated.  Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

scholarly journals Refinement of the critical genomic region for hypoglycaemia in the Chromosome 9p deletion syndrome

2019 ◽  
Vol 4 ◽  
pp. 149
Author(s):  
Indraneel Banerjee ◽  
Senthil Senniappan ◽  
Thomas W. Laver ◽  
Richard Caswell ◽  
Martin Zenker ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Chromosome 9 ◽  
Genetic Mechanism ◽  
Targeted Sequencing ◽  
Deletion Syndrome ◽  
Recessive Mutation ◽  
Potential Candidate ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Genetic Characteristics ◽  
Chromosome 9P

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome.  A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown.  Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated.  Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

scholarly journals Molecular mechanisms of congenital hyperinsulinism

2015 ◽  
Vol 54 (2) ◽  
pp. R119-R129 ◽  
Author(s):  
Sofia A Rahman ◽  
Azizun Nessa ◽  
Khalid Hussain
Keyword(s):  
Insulin Secretion ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
State Of The Art ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Genetic Abnormalities ◽  
Hydroxyacyl Coa Dehydrogenase

Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic β-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.

Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy

2020 ◽  
Vol 33 (5) ◽  
pp. 671-674
Author(s):  
Tashunka Taylor-Miller ◽  
Jayne Houghton ◽  
Paul Munyard ◽  
Yadlapalli Kumar ◽  
Clinda Puvirajasinghe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Newborn Period ◽  
Case Presentation ◽  
Male Baby ◽  
Common Causes ◽  
Compound Heterozygous Mutations

AbstractBackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

scholarly journals IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hong Lin ◽  
Yuan Yan ◽  
Yifan Luo ◽  
Wing Yan So ◽  
Xiayun Wei ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
High Fat Diet ◽  
E3 Ligase ◽  
Human Islets ◽  
Cop9 Signalosome ◽  
Congenital Hyperinsulinism ◽  
High Fat ◽  
Transcriptional Suppressor

AbstractCOP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1–CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2WT/K70E mice with partially disrupted binding of IP6, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4COP1 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4COP1 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2WT/K70E, high-fat diet-treated, and ob/ob mice. The CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4COP1-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP6-assisted CSN-COP1 competition. Deregulation of the IP6-CSN-CRL4COP1-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.

scholarly journals Mutations in UCP2 in Congenital Hyperinsulinism Reveal a Role for Regulation of Insulin Secretion

PLoS ONE ◽  
2008 ◽  
Vol 3 (12) ◽  
pp. e3850 ◽  
Author(s):  
M. Mar González-Barroso ◽  
Irina Giurgea ◽  
Fredéric Bouillaud ◽  
Andrea Anedda ◽  
Christine Bellanné-Chantelot ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Congenital Hyperinsulinism

Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia

2015 ◽  
Vol 28 (11-12) ◽  
Author(s):  
Mary B. Abraham ◽  
Vinutha B. Shetty ◽  
Glynis Price ◽  
Nicholas Smith ◽  
Martin de Bock ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Total Pancreatectomy ◽  
Efficacy And Safety ◽  
Neonatal Hypoglycaemia ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Common Cause

AbstractHyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous

Identification and confirmation of greenbug resistance loci in an advanced mapping population of sorghum

2017 ◽  
Vol 155 (10) ◽  
pp. 1610-1622 ◽  
Author(s):  
SOMASHEKHAR PUNNURI ◽  
YINGHUA HUANG
Keyword(s):  
Great Plains ◽  
Qtl Analysis ◽  
Mapping Population ◽  
Molecular Genetic ◽  
The United States ◽  
Chromosome 9 ◽  
Potential Candidate ◽  
Resistant Parent ◽  
Molecular Genetic Map ◽  
Greenbug Resistance

SUMMARYGreenbug infestations to sorghum can cause severe and above economic threshold damage in the Great Plains of the United States. The current study was conducted to identify quantitative trait loci (QTLs) and potential candidate genes residing within the QTL region responsible for greenbug resistance in an advanced mapping population. Inter-crossed populations are useful in detecting QTLs tightly linked to genetic markers with high resolution. In the current study, QTLs responsible for greenbug resistance in sorghum were mapped using an inter-cross population derived from two parents, BTx623 (greenbug-susceptible line) and PI 607900 (greenbug-resistant line). Molecular markers for 115 loci were used to construct a linkage map which eventually facilitated tagging portions of the sorghum genome regions responsible for greenbug resistance. The molecular genetic map covered all the chromosomes of sorghum with a total genome length of 963·0 cM. The advanced mapping population revealed and confirmed the location of greenbug resistance loci, which explained a high phenotypic variation from 72·9 to 80·9% of greenbug resistance. The loci for greenbug resistance were mapped to the region flanked by markers Starssbnm 93 and Starssbnm 102 on chromosome 9 with an increased allelic effect from the resistant parent. The locations of these loci were compared with a previous study on QTL analysis using an F2 mapping population. The results from the present study were in agreement with the findings in the F2 QTL analysis and identified QTLs had a better confidence interval. The markers/QTLs identified from the current study can be effectively utilized in marker-assisted selection and map-based cloning experiments.

Clinical presentation and treatment response to diazoxide in two siblings with congenital hyperinsulinism as a result of a novel compound heterozygous ABCC8 missense mutation

2017 ◽  
Vol 30 (4) ◽  
Author(s):  
Sonya Galcheva ◽  
Violeta Iotova ◽  
Sian Ellard ◽  
Sarah E. Flanagan ◽  
Irina Halvadzhiyan ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Index Patient ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Compound Heterozygosity ◽  
Clinical Heterogeneity ◽  
Intravenous Glucose ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Case Presentation ◽  
Compound Heterozygotes

AbstractBackground:Congenital hyperinsulinism (CHI) can present with considerable clinical heterogeneity which may be due to differences in the underlying genetic etiology. We present two siblings with hyperinsulinaemic hypoglycaemia (HH) and marked clinical heterogeneity caused by compound heterozygosity for the same two novelCase presentation:The index patient is a 3-year-old boy with hypoglycaemic episodes presenting on the first day of life. HH was diagnosed and treatment with intravenous glucose and diazoxide was initiated. Currently he has normal physical and neurological development, with occasional hypoglycaemic episodes detected following continuous fasting on treatment with diazoxide. The first-born 8-year-old sibling experienced severe postnatal hypoglycaemia, generalised seizures and severe brain damage despite diazoxide treatment. The latter was stopped at 6-months of age with no further registered hypoglycaemia. Genetic testing showed that both children were compound heterozygotes for two novelConclusions:These

scholarly journals Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency

2018 ◽  
Vol 89 (6) ◽  
pp. 413-422 ◽  
Author(s):  
Christopher E. Gibson ◽  
Kara E. Boodhansingh ◽  
Changhong Li ◽  
Laura Conlin ◽  
Pan Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Turner Syndrome ◽  
X Chromosome ◽  
Case Reports ◽  
Cytosolic Calcium ◽  
Congenital Hyperinsulinism ◽  
Kabuki Syndrome ◽  
Expected Frequency ◽  
Molecular Features ◽  
Mouse Islets

Background: Previous case reports have suggested a possible association of congenital hyperinsulinism with Turner syndrome. Objective: We examined the clinical and molecular features in girls with both congenital hyperinsulinism and Turner syndrome seen at The Children’s Hospital of Philadelphia (CHOP) between 1974 and 2017. Methods: Records of girls with hyperinsulinism and Turner syndrome were reviewed. Insulin secretion was studied in pancreatic islets and in mouse islets treated with an inhibitor of KDM6A, an X chromosome gene associated with hyperinsulinism in Kabuki syndrome. Results: Hyperinsulinism was diagnosed in 12 girls with Turner syndrome. Six were diazoxide-unresponsive; 3 had pancreatectomies. The incidence of Turner syndrome among CHOP patients with hyperinsulinism (10 of 1,050 from 1997 to 2017) was 48 times more frequent than expected. The only consistent chromosomal anomaly in these girls was the presence of a 45,X cell line. Studies of isolated islets from 1 case showed abnormal elevated cytosolic calcium and heightened sensitivity to amino acid-stimulated insulin release; similar alterations were demonstrated in mouse islets treated with a KDM6A inhibitor. Conclusion: These results demonstrate a higher than expected frequency of Turner syndrome among children with hyperinsulinism. Our data suggest that haploinsufficiency for KDM6A due to mosaic X chromosome monosomy may be responsible for hyperinsulinism in Turner syndrome.

Hyperinsulinemic Hypoglycemia

2016 ◽  
Author(s):  
Jean-Baptiste Arnoux ◽  
Pascal de Lonlay
Keyword(s):  
Insulin Secretion ◽  
Insulin Therapy ◽  
Insulin Signaling ◽  
Biological Evaluation ◽  
External Factors ◽  
Hyperinsulinemic Hypoglycemia ◽  
Diabetic Patients ◽  
Genetic Defects ◽  
Congenital Hyperinsulinism ◽  
Food Ingestion

Hypoglycemia is a frequent and often overlooked symptom. Indeed, most cases are related to insulin therapy in diabetic patients, to hormone deficiencies, or to very prolonged fasts. In other cases, however, unusual findings (unexplained hypoglycemia, especially if clinically severe, recurrent, postprandial, or in typical relationship to external factors such as food ingestion or exercise, or associated with hepatomegaly) should lead to a careful clinical and biological evaluation. Hyperinsulinemic hypoglycemia is a dysregulation of the glucose-induced insulin secretion. Besides insulinoma and genetic defects of the pancreatic ß-cell (congenital hyperinsulinism, CHI), some other pathophysiological mechanisms can lead to hypoglycemia with biological evidence for an involvement of the insulin signaling pathway (insulin-like substances, autoimmunity, and other).

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