A New Case of Congenital Malabsorptive Diarrhea and Diabetes Secondary to Mutant <i>Neurogenin-3</i>

Germán-Díaz, Marta; Rodriguez-Gil, Yolanda; Cruz-Rojo, Jaime; Charbit‐Henrion, Fabienne; Cerf‐Bensussan, Nadine; Manzanares, Javier Manzanares-López; Moreno-Villares, José Manuel

doi:10.1542/peds.2016-2210

Cited by 15 publications

(11 citation statements)

References 14 publications

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“…Mutations identified by WES were: a homozygous MALT1 mutation in two siblings with decreased number of Tregs, 34 a homozygous LRBA mutation in two other siblings, 37 a de novo gain-of-function mutation of STAT3 in one girl, and a homozygous MYO5B mutation in one boy in whom marked intestinal inflammation had erroneously led to ascribe the severe diarrhoea to an immune-mediated process. Mutations identified by TNGS included FOXP3 mutations in four boys, for three of whom only DNA was available and in one case normal number and phenotype of regulatory T cells but with abnormal suppressive function; a homozygous NEUROG3 mutation in one boy with chronic diarrhoea since the first months of life and type 1 diabetes since the age of one 38 ; compound heterozygous LRBA mutations in three patients, one boy with two missense mutation, and two siblings with one missense mutation and a large deletion [from exon 3 to exon 48]. As indicated above, this large deletion in LRBA had been missed by WES performed before TNGS.…”

Section: Resultsmentioning

confidence: 99%

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Charbit‐Henrion

Parlato

Hanein

et al. 2018

Journal of Crohn's and Colitis

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Background and AimsAn expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment.MethodsA total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally.ResultsMolecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES.ConclusionsOur results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

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Section: Resultsmentioning

confidence: 99%

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Charbit‐Henrion

Parlato

Hanein

et al. 2018

Journal of Crohn's and Colitis

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“…Previous studies have established that neurogenin 3 (Ngn3) is a key transcription factor for EEC differentiation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36. Consistent with the role of Ngn3 in EEC fate, overexpression of NGN3 in multiple systems has been shown to increase EEC numbers 37, 38.…”

mentioning

confidence: 80%

Human Intestinal Enteroids With Inducible Neurogenin-3 Expression as a Novel Model of Gut Hormone Secretion

Chang‐Graham

Danhof

Engevik

et al. 2019

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Enteroendocrine cells (EECs) are specialized epithelial cells that produce molecules vital for intestinal homeostasis, but because of their limited numbers, in-depth functional studies have remained challenging. Human intestinal enteroids (HIEs) that are derived from intestinal crypt stem cells are biologically relevant in an in vitro model of the intestinal epithelium. HIEs contain all intestinal epithelial cell types; however, similar to the intestine, HIEs spontaneously produce few EECs, which limits their study. Methods To increase the number of EECs in HIEs, we used lentivirus transduction to stably engineer jejunal HIEs with doxycycline-inducible expression of neurogenin-3 ( NGN3 ), a transcription factor that drives EEC differentiation (tet NGN3 -HIEs). We examined the impact of NGN3 induction on EECs by quantifying the increase in the enterochromaffin cells and other EEC subtypes. We functionally assessed secretion of serotonin and EEC hormones in response to norepinephrine and rotavirus infection. Results Treating tet NGN3 -HIEs with doxycycline induced a dose-dependent increase of chromogranin A (ChgA)-positive and serotonin-positive cells, showing increased enterochromaffin cell differentiation. Despite increased ChgA-positive cells, other differentiated cell types of the epithelium remained largely unchanged by gene expression and immunostaining. RNA sequencing of doxycycline-induced tet NGN3 -HIEs identified increased expression of key hormones and enzymes associated with several other EEC subtypes. Doxycycline-induced tet NGN3 -HIEs secreted serotonin, monocyte chemoattractant protein-1, glucose-dependent insulinotropic peptide, peptide YY, and ghrelin in response to norepinephrine and rotavirus infection, further supporting the presence of multiple EEC types. Conclusions We have combined HIEs and inducible- NGN3 expression to establish a flexible in vitro model system for functional studies of EECs in enteroids and advance the molecular and physiological investigation of EECs.

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“…Despite these observations, it remains unclear whether NEUROG3 is absolutely required for beta cell development in humans. In contrast to mouse studies, all reported patients with biallelic mutations in NEUROG3 have functional endocrine cells capable of releasing C-peptide despite severe enteric anendocrinosis from childhood [ 13 ]. All of these cases indicate the presence of insulin-secreting cells, and the reason for this is still elusive.…”

Section: Biological Properties Of Pdx1 Neurog3 and Mafamentioning

confidence: 99%

PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration

Zhu

Liu

Zhou³

et al. 2017

Stem Cell Res Ther

239

169

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Transcription factors regulate gene expression through binding to specific enhancer sequences. Pancreas/duodenum homeobox protein 1 (PDX1), Neurogenin-3 (NEUROG3), and V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) are transcription factors critical for beta cell development and maturation. NEUROG3 is expressed in endocrine progenitor cells and controls islet differentiation and regeneration. PDX1 is essential for the development of pancreatic exocrine and endocrine cells including beta cells. PDX1 also binds to the regulatory elements and increases insulin gene transcription. Likewise, MAFA binds to the enhancer/promoter region of the insulin gene and drives insulin expression in response to glucose. In addition to those natural roles in beta cell development and maturation, ectopic expression of PDX1, NEUROG3, and/or MAFA has been successfully used to reprogram various cell types into insulin-producing cells in vitro and in vivo, such as pancreatic exocrine cells, hepatocytes, and pluripotent stem cells. Here, we review biological properties of PDX1, NEUROG3, and MAFA, and their applications and limitations for beta cell regenerative approaches. The primary source literature for this review was acquired using a PubMed search for articles published between 1990 and 2017. Search terms include diabetes, insulin, trans-differentiation, stem cells, and regenerative medicine.

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A New Case of Congenital Malabsorptive Diarrhea and Diabetes Secondary to Mutant Neurogenin-3

Cited by 15 publications

References 14 publications

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Human Intestinal Enteroids With Inducible Neurogenin-3 Expression as a Novel Model of Gut Hormone Secretion

PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration

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