What is new about the genetic background of Hirschsprung disease?

Luzón-Toro, Berta; Villalba-Benito, Leticia; Torroglosa, Ana; Fernández, Raquel M.; Antiñolo, Guillermo; Borrego, Salud

doi:10.1111/cge.13615

Cited by 22 publications

(21 citation statements)

References 167 publications

(337 reference statements)

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“…Genetically, HSCR is a rare, multifactorial disorder with an incidence of 1:5,000 live births, showing male sex preponderance, incomplete penetrance, and variable expressivity [1,8,9]. To…”

Section: Introductionmentioning

confidence: 99%

“…Genetically, HSCR is a rare, multifactorial disorder with an incidence of 1:5,000 live births, showing male sex preponderance, incomplete penetrance, and variable expressivity [ 1 , 8 , 9 ]. To date, more than 20 genes have been identified and replicated that affect signaling cascades crucial for ENS development.…”

Section: Introductionmentioning

confidence: 99%

“…The major susceptibility locus is RET as mutations account for up to 50% of familial and 20% of sporadic HSCR cases. To date, mutations in other HSCR risk genes have been identified in about 5% of patients [ 9 , 10 ]. However, variants in these established genes account for only 30% of patients, but many more genes have been implicated in its pathoetiology [ 9 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease

et al. 2020

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Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.

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“…For most isolated and sporadic forms, a complex genetic basis has been proposed, where the presence of several genetic variants acting in an additive or multiplicative manner leads to the disease [4]. The RET proto-oncogene (OMIM 164761) is the main gene associated with HSCR [5][6][7], although there are many other genes related to the disease, among which most are involved in the development of the Enteric Nervous System (ENS) [8].…”

Section: Introductionmentioning

confidence: 99%

Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease

Torroglosa

Villalba-Benito

Fernández

et al. 2020

IJMS

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Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic mechanisms are gaining increasing relevance. In an effort to better understand the epigenetic basis of HSCR, we have performed an analysis for the identification of long non-coding RNAs (lncRNAs) by qRT-PCR in enteric precursor cells (EPCs) from controls and HSCR patients. We aimed to test the presence of a set lncRNAs among 84 lncRNAs in human EPCs, which were previously related with crucial cellular processes for ENS development, as well as to identify the possible differences between HSCR patients and controls. As a result, we have determined a set of lncRNAs with positive expression in human EPCs that were screened for mutations using the exome data from our cohort of HSCR patients to identify possible variants related to this pathology. Interestingly, we identified three lncRNAs with different levels of their transcripts (SOCS2-AS, MEG3 and NEAT1) between HSCR patients and controls. We propose such lncRNAs as possible regulatory elements implicated in the onset of HSCR as well as potential biomarkers of this pathology.

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“…Familial and syndromic HSCR show a Mendelian pattern of inheritance. However, the etiology of the sporadic HSCR seems to be intricate, presenting a non-Mendelian type inheritance and involving many genetic and environmental factors (4). So far, more than 20 HSCR susceptibility genes have been found to be associated with the development of ENS (5,6).…”

Section: Introductionmentioning

confidence: 99%

NOX5 is Expressed Aberrantly but Not a Critical Pathogenetic Gene in Hirschsprung Disease

Wang

Xiao

Meng

et al. 2020

Preprint

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Background:Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of intramural ganglion cells in the distal gastrointestinal tract (GI), which results in tonic contraction of the aganglionic gut segment and functional intestinal obstruction. Recent studies have suggested NADPH oxidase 5 (NOX5) as a candidate risk gene for HSCR. In this study, we examined the function of NOX5 to verify its role in the development of enteric nervous system (ENS).Methods: HSCR tissue specimens (n = 10) were collected at the time of pull-through surgery and control specimens (n = 10) were obtained at the time of colostomy closure in patients. The NOX5 expression in aganglionic and ganglionic segments of HSCR colon and normal colon were analyzed by immunohistochemistry (IHC), western blot and RT-qPCR. The gene expression levels and spatiotemporal expression spectrum of NOX5 in different development stages of zebrafish embryo were investigated using real-time quantitative PCR (RT-qPCR) and in-situ hybridization (ISH). The enteric nervous system in NOX5 Morpholino (MO) knockdown and wild type (WT) zebrafish embryo was analyzed by whole-mount immunofluorescence (IF). Intestinal transit assay was performed to analyze the gastrointestinal motility in NOX5 knockdown and control larvae.ResultsNOX5 is strongly expressed in the ganglion cells in the proximal segment of HSCR colons and all segments of normal colons. Moreover, the expression of NOX5 is markedly decreased in the aganglionic segment of HSCR colon compared to the ganglionic segment. In zebrafish, NOX5 mRNA level is the highest in one cell stage embryos and it is decreased by the development of the embryos. Interestingly, the expression of NOX5 appears to be enriched in the nervous system. However, the number of neurons in the GI tract and the GI motility were not affected upon NOX5 knockdown.ConclusionsNOX5 may play a role in the early development of zebrafish embryo, but not required for the ENS development and loss of NOX5 didn’t affect the GI motility in zebrafish. Nevertheless, we demonstrated that NOX5 specifically expressed in the ganglionic cell in colon tissue and markedly decreased in the aganglionic segment.

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What is new about the genetic background of Hirschsprung disease?

Cited by 22 publications

References 167 publications

A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease

Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease

NOX5 is Expressed Aberrantly but Not a Critical Pathogenetic Gene in Hirschsprung Disease

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