Congenital Hyperinsulinism due to mutations in HNF4A and HADH

Kapoor, Ritika R; Heslegrave, Amanda; Hussain, Khalid

doi:10.1007/s11154-010-9148-y

Cited by 23 publications

(18 citation statements)

References 40 publications

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“…HADH encodes hydroxyacyl-CoA dehydrogenase, an important enzyme and negative regulator of glutamate dehydrogenase (GDH) and insulin secretion. Expression of HADH in islets has been shown to be beta cell specific (Kapoor et al 2010;Pepin et al 2010), and indeed, knockdown of HADH in rat 832/13 beta cells increases insulin secretion (Pepin et al 2010). Surprisingly, our combined transcriptomic analyses and in situ (ViewRNA) validation of HADH revealed shared expression in beta and delta cells.…”

Section: Discussionmentioning

confidence: 71%

“…Notable examples included beta and delta cell expression of the congenital hyperinsulinemia (CHI) gene HADH and alpha and PP/gamma cell expression of the ARX transcription factor (Liu et al 2011). HADH is typically associated with beta cell expression and, when mutated, leads to insulin hypersecretion and CHI (Kapoor et al 2010;Pepin et al 2010); these data implicate the delta cell in the molecular genetics of CHI. Misexpression of ARX has been shown to convey both alpha and PP/gamma cell features to cells (Collombat et al 2007), suggesting that its expression in each cell type is important for identity and function.…”

Section: Differential Expression Analyses Reveal Islet Cell-type-specmentioning

confidence: 99%

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Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

et al. 2016

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Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type-specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis.[Supplemental material is available for this article.]Pancreatic islets of Langerhans are clusters of at least four different hormone-secreting endocrine cell types that elicit coordinatedbut distinct-responses to maintain glucose homeostasis. As such, they are central to diabetes pathophysiology. On average, human islets consist mostly of beta (54%), alpha (35%), and delta (11%) cells; up to a few percent gamma/pancreatic polypeptide (PP) cells; and very few epsilon cells (Brissova et al. 2005;Cabrera et al. 2006;Blodgett et al. 2015). Human islet composition is neither uniform nor static but varies between individuals and across regions of the pancreas (Brissova et al. 2005;Cabrera et al. 2006;Blodgett et al. 2015). Cellular heterogeneity complicates molecular studies of whole human islets and may mask important role(s) for less common cells in the population (Dorrell et al. 2011b;Bramswig et al. 2013;Nica et al. 2013;Blodgett et al. 2015;Liu and Trapnell 2016). Moreover, it complicates attempts to identify epigenetic and transcriptional signatures distinguishing diabetic from nondiabetic (ND) islets, leading to inconsistent reports of genes and pathways affected (Gunton et al. 2005;Marselli et al. 2010;Taneera et al. 2012;Dayeh et al. 2014). Conventional sorting and enrichment techniques are unable to specifically purify each human islet cell type (Dorrell et al. 2008;Nica et al. 2013;Bramswig et al. 2013;Hrvatin et al. 2014;Blodgett et al. 2015), thus a precise understanding of the transcriptiona...

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Section: Discussionmentioning

confidence: 71%

Section: Differential Expression Analyses Reveal Islet Cell-type-specmentioning

confidence: 99%

Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

et al. 2016

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“…HNF4A gene encodes for the transcription factor hepatocyte nuclear factor 4 alpha (HNF-4α), which belongs to the nuclear hormone receptor superfamily and is required in the pancreatic β-cell for regulation of the pathway of insulin secretion. Lossof-function HNF4A mutations cause maturity-onset diabetes of the young type 1 (MODY1), which is characterized by progressive β-cell destruction and failure of glucose-induced insulin secretion (70,71).…”

Section: Introductionmentioning

confidence: 99%

Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management

Senniappan

Balasubramaniam

James

et al. 2012

J of Inher Metab Disea

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122

121

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Hyperinsulinaemic hypoglycaemia (HH) is due to the unregulated secretion of insulin from pancreatic β‐cells. A rapid diagnosis and appropriate management of these patients is essential to prevent the potentially associated complications like epilepsy, cerebral palsy and neurological impairment. The molecular basis of HH involves defects in key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2) which regulate insulin secretion. The most severe forms of HH are due to loss of function mutations in ABCC8/KCNJ11 which encode the SUR1 and KIR6.2 components respectively of the pancreatic β‐cell KATP channel. At a histological level there are two major forms (diffuse and focal) each with a different genetic aetiology. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localised to a small region of the pancreas. The focal form can now be accurately localised pre‐operatively using a specialised positron emission tomography scan with the isotope Fluroine‐18L‐3, 4‐dihydroxyphenyalanine (18F‐DOPA‐PET). Focal lesionectomy can provide cure from the hypoglycaemia. However the diffuse form is managed medically or by near total pancreatectomy (with high risk of diabetes mellitus). Recent advances in molecular genetics, imaging with 18F‐DOPA‐PET/CT and novel surgical techniques have changed the clinical approach to patients with HH.

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“…Gene ontology analyses’ results show that this gene is closely related to cellular metabolic process, including lipid metabolic process; response to hormone stimulus; fatty acid metabolic; and beta-oxidation process, and negatively regulates insulin secretion. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia and hyperinsulinism 28–30. However, there is no research report so far about HADHSC in human cancer.…”

Section: Discussionmentioning

confidence: 99%

Identification of Gene Signatures Used to Recognize Biological Characteristics of Gastric Cancer upon Gene Expression Data

et al. 2014

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High-throughput gene expression microarrays can be examined by machine-learning algorithms to identify gene signatures that recognize the biological characteristics of specific human diseases, including cancer, with high sensitivity and specificity. A previous study compared 20 gastric cancer (GC) samples against 20 normal tissue (NT) samples and identified 1,519 differentially expressed genes (DEGs). In this study, Classification Information Index (CII), Information Gain Index (IGI), and RELIEF algorithms are used to mine the previously reported gene expression profiling data. In all, 29 of these genes are identified by all three algorithms and are treated as GC candidate biomarkers. Three biomarkers, COL1A2, ATP4B, and HADHSC, are selected and further examined using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining in two independent sets of GC and normal adjacent tissue (NAT) samples. Our study shows that COL1A2 and HADHSC are the two best biomarkers from the microarray data, distinguishing all GC from the NT, whereas ATP4B is diagnostically significant in lab tests because of its wider range of fold-changes in expression. Herein, a data-mining model applicable for small sample sizes is presented and discussed. Our result suggested that this mining model may be useful in small sample-size studies to identify putative biomarkers and potential biological features of GC.

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Congenital Hyperinsulinism due to mutations in HNF4A and HADH

Cited by 23 publications

References 40 publications

Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management

Identification of Gene Signatures Used to Recognize Biological Characteristics of Gastric Cancer upon Gene Expression Data

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