Chromosome 11p15 Paternal Isodisomy in Focal Forms of Neonatal Hyperinsulinism

Damaj, Léna; Lorc’h, Marc Le; Verkarre, Virginie; Werl, C.; Hubert, Laurence; Nihoul‐Feketé, Claire; Aigrain, Yves; Keyzer, Yves de; Romana, Serge; Bellanné‐Chantelot, Christine; Lonlay, Pascale de; Jaubert, Françis

doi:10.1210/jc.2008-0673

Cited by 63 publications

(69 citation statements)

References 23 publications

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“…The focal lesions are characterised by nodular hyperplasia of islet-like cell clusters with ductuloinsular complexes and scattered giant b-cell nuclei with normal surrounding tissue (16). The focal CHI results from a paternally inherited heterozygous ABCC8/KCNJ11 mutation together with a somatic loss of the maternal chromosome in the 11p15 region (most likely caused by paternal isodisomy) (16,17).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The focal CHI results from a paternally inherited heterozygous ABCC8/KCNJ11 mutation together with a somatic loss of the maternal chromosome in the 11p15 region (most likely caused by paternal isodisomy) (16,17). The resulting loss of heterozygosity (LOH) renders the b-cells biallelic for the abnormal foci, altering the K ATP channel and resulting in dysregulated insulin secretion within the focal lesion (16,17,18). The consequent imbalance in the expression of adjacent imprinted genes implicated in cell proliferation (such as CDKN1C and H19 normally expressed from the maternal allele and IGF2 paternally expressed) within the 11p15.5 region leads to focal islet cell adenomatous hyperplasia (19,20,21,22).…”

Section: Introductionmentioning

confidence: 99%

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Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Arya

Güemes

Nessa

et al. 2014

European Journal of Endocrinology

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Context: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. Objective: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. Design: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. Results: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 L-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography ( 18 F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (nZ8) or 18

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Arya

Güemes

Nessa

et al. 2014

European Journal of Endocrinology

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“…The diffuse form is most often caused by recessive mutations in ABCC8 or KCNJ11, while in the focused form heterozygous germline mutations are observed, which are inherited from the father, with a simultaneous loss of the maternal chromosome 11 in the region 11p15.1 to 11p15.5 [8]. The loss of that region in pancreatic progenitor cells is compensated by the duplication of genetic material of the father (somatic paternal uniparental disomy) [9].…”

Section: Abcc8/kcnj11mentioning

confidence: 99%

“…Podczas gdy w patogenezie postaci zogniskowanej obserwuje się występowanie mutacji germinalnych w układzie heterozygotycznym, dziedziczonych od ojca z jednoczesną utratą matczynego chromosomu 11 w regionie p15.1 do p.15.5 [8]. Utrata wymienionego regionu w obrębie komórek progenitorowych trzustki zostaje skompensowana przez duplikację materiału genetycznego ojca, zatem somatyczną ojcowską disomię jednorodzicielską [9].…”

Section: Prace Poglądoweunclassified

Nieinsulinowa hipoglikemia trzustkowa u dorosłych — przegląd genetyki

Gilis‐Januszewska

Piątkowski

Skalniak

et al. 2015

Endokrynologia Polska

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Hyperinsulinaemic hypoglycaemia (HH) is also classically referred to as "nesidioblastosis". Heterogeneous clinical manifestation of the disease causes risk of late diagnosis or even misdiagnosis. In infants and children, it can lead to serious and permanent damage to the central nervous system, which leads to the manifesting mental retardation. HH is characterised by unregulated insulin secretion from pancreatic β-cells. This effect has been correlated with nine genes: ABCC8, KCNJ11, GCK, GLUD-1, HADH1, SLC16A1, HNF4A, HNF1A, and UCP2. Mutations in these genes were found in approximately 48% of cases. The genetic background of the remaining cases is unknown. Understanding the genetic basis of familial hyperinsulinism has changed the early look at the disease. It has allowed for the differentiation of specific types of the disease. Depending on which of the nine disease-associated loci bears a pathogenic mutation, they differ in phenotype and pattern of inheritance. This review provides a brief overview of the genetic mechanisms of HH and its possible clinical presentations. StreszczenieHipogligemia hiperinsulinemiczna (HH) określana jest również terminem "nesidioblastoza". Różnorodna kliniczna manifestacja choroby powoduje ryzyko późnej diagnozy, a nawet braku rozpoznania. U niemowląt i dzieci nesidioblastoza prowadzić może do ciężkich i trwałych uszkodzeń centralnego systemu nerwowego, manifestujących się w postaci niedorozwoju umysłowego. Hipogligemia hiperinsulinemiczna charakteryzuje się nieuregulowanym wydzielaniem insuliny przez komórki β trzustki. Efekt ten powiązany został z dziewięcioma genami: ABCC8, KCNJ11, GCK, GLUD-1, HADH1, SLC16A1, HNF4A, HNF1A i UCP2. Mutacje występujące w wymienionych genach znajdowane są u 48% chorych. Genetyczne podłoże pozostałych przypadków pozostaje nieznane. Zrozumienie genetycznej przyczyny rodzinnej postaci hiperisnulinizmu zmieniło sposób, w jaki postrzegano chorobę. Pozwoliło na wyróżnienie poszczególnych jej typów. W zależność od tego, w którym z dziewięciu zasocjowanych z chorobą loci występuje patogenna mutacja, typy różnią się fenotypem i sposobem dziedziczenia. Praca stanowi krótki przegląd genetycznych patomechanizmów choroby obserwowanych w HH oraz ich możliwych prezentacji klinicznych. (Endokrynol Pol 2015; 66 (4): 344-354)

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Unravelling the genetic causes of mosaic islet morphology in congenital hyperinsulinism

Houghton

Banerjee

Shaikh

et al. 2019

The Journal of Pathology CR

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Congenital hyperinsulinism (CHI) causes dysregulated insulin secretion which can lead to life‐threatening hypoglycaemia if not effectively managed. CHI can be sub‐classified into three distinct groups: diffuse, focal and mosaic pancreatic disease. Whilst the underlying causes of diffuse and focal disease have been widely characterised, the genetic basis of mosaic pancreatic disease is not known. To gain new insights into the underlying disease processes of mosaic‐CHI we studied the islet tissue histopathology derived from limited surgical resection from the tail of the pancreas in a patient with CHI. The underlying genetic aetiology was investigated using a combination of high depth next‐generation sequencing, microsatellite analysis and p57kip2 immunostaining. Histopathology of the pancreatic tissue confirmed the presence of a defined area associated with marked islet hypertrophy and a cytoarchitecture distinct from focal CHI but compatible with mosaic CHI localised to a discrete region within the pancreas. Analysis of DNA extracted from the lesion identified a de novo mosaic ABCC8 mutation and mosaic paternal uniparental disomy which were not present in leukocyte DNA or the surrounding unaffected pancreatic tissue. This study provides the first description of two independent disease‐causing somatic genetic events occurring within the pancreas of an individual with localised mosaic CHI. Our findings increase knowledge of the genetic causes of islet disease and provide further insights into the underlying developmental changes associated with β‐cell expansion in CHI.

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Chromosome 11p15 Paternal Isodisomy in Focal Forms of Neonatal Hyperinsulinism

Cited by 63 publications

References 23 publications

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Nieinsulinowa hipoglikemia trzustkowa u dorosłych — przegląd genetyki

Unravelling the genetic causes of mosaic islet morphology in congenital hyperinsulinism

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