Expression profiling the developing mammalian enteric nervous system identifies novel markers and candidate Hirschsprung disease genes

Hirschsprung is a birth defect of Enteric Nervous System (ENS) which is characterized by the absence of enteric neurons along the length of intestine. Hirschsprung is one of the complex diseases which has become a important topic of human genetics. In this article we have focused on RET gene mutation that is most common cause of HSCR disease. Out of seven mutations in RET gene, one mutation S339L is found to be tolerated and have no effect on protein function.

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Size matters: large copy number losses reveal novel Hirschsprung disease genes

10.1101/2020.11.02.20221481 ◽

2020 ◽

Author(s):

Laura Kuil ◽

Katherine C. MacKenzie ◽

Clara S Tang ◽

Jonathan D. Windster ◽

Thuy Linh Le ◽

...

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Copy Number ◽

De Novo ◽

Hirschsprung Disease ◽

Genetic Alterations ◽

Nervous System Development ◽

Disease Genes ◽

Enteric Ganglia ◽

Coding Variants

AbstractBackgroundHirschsprung disease (HSCR) is characterized by absence of ganglia in the intestine. Approximately 18% of patients have additional anatomical malformations or neurological symptoms (HSCR-AAM). HSCR is a complex genetic disease in which the loss of enteric ganglia stems from a combination of genetic alterations: rare coding variants, predisposing haplotypes and Copy Number Variation (CNV). Pinpointing the responsible culprits within a large CNV is challenging as often many genes are affected. We investigated if we could find deleterious CNVs and if we could identify the genes responsible for the aganglionosis.ResultsDeleterious CNVs were detected in three groups of patients: HSCR-AAM, HSCR patients with a confirmed causal genetic variant and HSCR-isolated patients without a known causal variant and controls. Predisposing haplotypes were determined, confirming that every HSCR subgroup had increased contributions of predisposing haplotypes, but their contribution was highest in isolated HSCR patients without RET coding variants. CNV profiling proved that HSCR-AAM patients had larger copy number losses. Gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics were used to determine plausible candidate genes in Copy Number Losses. Validation in zebrafish using CRISPR/Cas9 targeting confirmed the contribution of UFD1L, TBX2, SLC8A1 and MAPK8 to ENS development. In addition, we revealed epistasis between reduced Ret and Gnl1 expression in vivo.ConclusionRare large Copy Number losses - often de novo - contribute to the disease in HSCR-AAM patients specifically. We proved the involvement of five genes in enteric nervous system development and Hirschsprung disease.

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“Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review

Clinical Epigenetics ◽

10.1186/s13148-019-0718-x ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 6

Author(s):

Emilie G. Jaroy ◽

Lourdes Acosta-Jimenez ◽

Ryo Hotta ◽

Allan M. Goldstein ◽

Ragnhild Emblem ◽

...

Keyword(s):

Gene Expression ◽

Nervous System ◽

Enteric Nervous System ◽

Hirschsprung's Disease ◽

Hirschsprung’S Disease ◽

Current Knowledge ◽

Hirschsprung Disease ◽

Gut Development ◽

Dna And Rna ◽

Expression Of Genes

Abstract Hirschsprung disease is a neurocristopathy, characterized by aganglionosis in the distal bowel. It is caused by failure of the enteric nervous system progenitors to migrate, proliferate, and differentiate in the gut. Development of an enteric nervous system is a tightly regulated process. Both the neural crest cells and the surrounding environment are regulated by different genes, signaling pathways, and morphogens. For this process to be successful, the timing of gene expression is crucial. Hence, alterations in expression of genes specific for the enteric nervous system may contribute to the pathogenesis of Hirschsprung’s disease. Several epigenetic mechanisms contribute to regulate gene expression, such as modifications of DNA and RNA, histone modifications, and microRNAs. Here, we review the current knowledge of epigenetic and epitranscriptomic regulation in the development of the enteric nervous system and its potential significance for the pathogenesis of Hirschsprung’s disease. We also discuss possible future therapies and how targeting epigenetic and epitranscriptomic mechanisms may open new avenues for novel treatment.

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Developmental markers of ganglion cells in the enteric nervous system and their application for evaluation of Hirschsprung disease

Pathology International ◽

10.1111/pin.12191 ◽

2014 ◽

Vol 64 (9) ◽

pp. 432-442 ◽

Cited By ~ 6

Author(s):

Hitomi Kawai ◽

Kaishi Satomi ◽

Yukio Morishita ◽

Yoshihiko Murata ◽

Masato Sugano ◽

...

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Ganglion Cells ◽

Hirschsprung Disease

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Significant Association of rs2147555 Genetic Polymorphism in the EDNRB Gene with Hirschsprung Disease in Southern Chinese Children

BioMed Research International ◽

10.1155/2020/5956412 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Yi Zheng ◽

ChaoTing Lan ◽

Ning Wang ◽

Xiaogang Xu ◽

Tuqun Hu ◽

...

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Significant Risk ◽

Hirschsprung Disease ◽

Recessive Model ◽

Abnormal Development ◽

Chinese Han ◽

Southern Chinese ◽

Ednrb Gene ◽

Genetic And Environmental Factors

Hirschsprung disease (HSCR) is a human birth defect at the clinical setting, usually characterized by an absent enteric nervous system (ENS) from the distal bowel. The majority of HSCR cases represent a complex disorder resulting from the interaction of multiple genetic and environmental factors. Genetic events have been described to be involved in the abnormal development of the enteric nervous system. Although variants in several genes like RET and EDNRB have been suggested to contribute major risks to HSCR, very little is known about their involvement in the onset of HSCR. Here, we studied a large Chinese Han cohort consisting of 1,470 HSCR patients and 1,473 non-HSCR controls to further test whether there are more variants in EDNRB associated with HSCR. Our results provided the first evidence that rs2147555 in EDNRB confers a significant risk of HSCR in a Chinese Han population for both allelic frequencies ( P = 4.16 × 10 − 3 ; OR = 1.29 ) and genotypic frequencies assuming either a dominant or recessive model ( P = 0.011 and P = 0.027 , respectively). When different subtypes of HSCR cases were analyzed, the association remained significant ( OR = 1.33 , P = 0.003 for short-segment HSCR; OR = 1.34 , P = 0.044 for long segment HSCR).

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NTF-3, a gene involved in the enteric nervous system development, as a candidate gene for Hirschsprung disease

Journal of Pediatric Surgery ◽

10.1016/j.jpedsurg.2008.02.076 ◽

2008 ◽

Vol 43 (7) ◽

pp. 1308-1311 ◽

Cited By ~ 21

Author(s):

Macarena Ruiz-Ferrer ◽

Raquel M. Fernandez ◽

Guillermo Antiñolo ◽

Manuel Lopez-Alonso ◽

Salud Borrego

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Candidate Gene ◽

System Development ◽

Hirschsprung Disease ◽

Nervous System Development ◽

Enteric Nervous System Development

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Host Gut Motility and Bacterial Competition Drive Instability in a Model Intestinal Microbiota

10.1101/052985 ◽

2016 ◽

Author(s):

Travis J. Wiles ◽

Matthew L. Jemielita ◽

Ryan P. Baker ◽

Brandon H. Schlomann ◽

Savannah L. Logan ◽

...

Keyword(s):

Nervous System ◽

Gut Microbiota ◽

Enteric Nervous System ◽

Bacterial Species ◽

Stochastic Perturbation ◽

Hirschsprung Disease ◽

Light Sheet ◽

Mitigation Strategies ◽

Gut Motility ◽

Bacterial Competition

AbstractThe gut microbiota is a complex consortium of microorganisms with the ability to influence important aspects of host health and development. Harnessing this ‘microbial organ’ for biomedical applications requires clarifying the degree to which host and bacterial factors act alone or in combination to govern the stability of specific lineages. To address this we combined bacteriological manipulation and light sheet fluorescence microscopy to monitor the dynamics of a defined two-species microbiota within the vertebrate gut. We observed that the interplay between each population and the gut environment produced distinct spatiotemporal patterns. Consequently, one species dominates while the other experiences dramatic collapses that are well fit by a stochastic mathematical model. Modeling revealed that bacterial competition could only partially explain the observed phenomena, suggesting that a host factor is also important in shaping the community. We hypothesized the host determinant to be gut motility, and tested this mechanism by measuring colonization in hosts with enteric nervous system dysfunction due to mutation in the Hirschsprung disease locus ret. In mutant hosts we found reduced gut motility and, confirming our hypothesis, robust coexistence of both bacterial species. This study provides evidence that host-mediated spatial structuring and stochastic perturbation of communities along with bacterial competition drives population dynamics within the gut. In addition, this work highlights the capacity of the enteric nervous system to affect stability of gut microbiota constituents, demonstrating that the ‘gut-brain axis’ is bidirectional. Ultimately, these findings will help inform disease mitigation strategies focused on engineering the intestinal ecosystem.

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