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Karim A, Tang CSM, Tam PKH. The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications. Front Pediatr 2021; 9:638093. [PMID: 34422713 PMCID: PMC8374333 DOI: 10.3389/fped.2021.638093] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 07/02/2021] [Indexed: 12/25/2022] Open
Abstract
Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500-5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.
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Affiliation(s)
- Anwarul Karim
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Clara Sze-Man Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Li Dak-Sum Research Center, The University of Hong Kong—Karolinska Institute Collaboration in Regenerative Medicine, Hong Kong, China
| | - Paul Kwong-Hang Tam
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Li Dak-Sum Research Center, The University of Hong Kong—Karolinska Institute Collaboration in Regenerative Medicine, Hong Kong, China
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Congenital central hypoventilation syndrome: An overview of etiopathogenesis, associated pathologies, clinical presentation, and management. Auton Neurosci 2017; 210:1-9. [PMID: 29249648 DOI: 10.1016/j.autneu.2017.11.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 10/10/2017] [Accepted: 11/12/2017] [Indexed: 12/19/2022]
Abstract
Congenital central hypoventilation syndrome (CCHS), known colloquially as Ondine's curse, is a rare disorder characterized by impaired autonomic control of breathing during sleep from the loss of vagal input and diminished sensitivity of CO2 receptors in the medulla. CCHS correlates to the malformation of the neural crest located in the brainstem; this consequently affects the loss of sensitivity of CO2 chemoreceptors, bringing about hypoventilation during sleep. The primary cause of CCHS is the mutation of the paired-like homeobox PHO2XB gene, found in 90% of the patients. This mutation not only affects breathing but also drives neurological abnormalities such as autonomic and neurocognitive dysfunction. Though typically congenital, there have been late-onset (i.e., acquired) cases reported. It is vital for physicians and clinicians to be able to diagnose CCHS due to its similar presentation to other syndromes and disorders, which may cause it to be misdiagnosed and may account for its deleterious effects. CCHS can lead to a constellation of symptoms, and consideration of diseases that present concomitantly with CCHS affords us a better understanding of the etiology of this illness. Although a rare syndrome, we aim to review the current literature to emphasize the pathogenesis, etiology, clinical presentation, symptoms, diagnosis, and current treatment methods of CCHS for clinicians to better identify and understand this condition.
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Badal B, Wilsey MJ, Karjoo S. Hemophagocytic lymphohistiocytosis presenting in a pediatric patient with near total colonic and small bowel aganglionosis: a case report. J Med Case Rep 2017; 11:244. [PMID: 28854959 PMCID: PMC5577747 DOI: 10.1186/s13256-017-1390-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 07/13/2017] [Indexed: 11/15/2022] Open
Abstract
Background Total colonic and small bowel aganglionosis is a rare condition typically requiring intestinal transplant for long-term survival. There have not been any previously reported cases of near total intestinal aganglionosis complicated by concerns for hemophagocytic lymphohistiocytosis and need for both multivisceral organ transplant and hematopoietic stem cell transplant. Case presentation Our patient is a 35-month-old Egyptian boy who presented with bilious emesis and failure to pass meconium shortly after birth. After evaluation, he was found to have near total colonic and small bowel aganglionosis up to the ligament of Treitz. When he was transferred to our tertiary facility, he was already diagnosed as having aganglionosis of total colon and partial small bowel whose case is complicated by the concern for hemophagocytic lymphohistiocytosis. He was not able to absorb any substantial nutrition enterally and was stabilized on long-term total parenteral nutrition which resulted in total parenteral nutrition-induced liver injury. While awaiting evaluation for liver and bowel transplant, he developed concerning symptoms consistent with hemophagocytic lymphohistiocytosis. He presents a complex challenge creating difficulty with management of whether to proceed with bowel transplant as a result of near-total intestinal aganglionosis or hematopoietic stem cell transplant for treatment of hemophagocytic lymphohistiocytosis. In this case, the transplant team proceeded with visceral transplant first, however he did not survive. Conclusions This presentation of aganglionosis of total colon and partial small bowel complicated by the concern for hemophagocytic lymphohistiocytosis is unique to medical literature. For many physicians involved it is hard to determine how best to proceed with next steps in care.
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Affiliation(s)
- Brittany Badal
- Johns Hopkins All Children's Hospital, 501 6th Ave S, St. Petersburg, FL, 33701, USA.
| | - Michael J Wilsey
- Johns Hopkins All Children's Hospital, 501 6th Ave S, St. Petersburg, FL, 33701, USA
| | - Sara Karjoo
- Johns Hopkins All Children's Hospital, 501 6th Ave S, St. Petersburg, FL, 33701, USA
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Gordon C, Petit F, Kroisel P, Jakobsen L, Zechi-Ceide R, Oufadem M, Bole-Feysot C, Pruvost S, Masson C, Tores F, Hieu T, Nitschké P, Lindholm P, Pellerin P, Guion-Almeida M, Kokitsu-Nakata N, Vendramini-Pittoli S, Munnich A, Lyonnet S, Holder-Espinasse M, Amiel J. Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears. Am J Hum Genet 2013; 93:1118-25. [PMID: 24268655 DOI: 10.1016/j.ajhg.2013.10.023] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 10/11/2013] [Accepted: 10/22/2013] [Indexed: 10/26/2022] Open
Abstract
Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway.
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Butler Tjaden NE, Trainor PA. The developmental etiology and pathogenesis of Hirschsprung disease. Transl Res 2013; 162:1-15. [PMID: 23528997 PMCID: PMC3691347 DOI: 10.1016/j.trsl.2013.03.001] [Citation(s) in RCA: 159] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 02/25/2013] [Accepted: 03/01/2013] [Indexed: 02/08/2023]
Abstract
The enteric nervous system is the part of the autonomic nervous system that directly controls the gastrointestinal tract. Derived from a multipotent, migratory cell population called the neural crest, a complete enteric nervous system is necessary for proper gut function. Disorders that arise as a consequence of defective neural crest cell development are termed neurocristopathies. One such disorder is Hirschsprung disease (HSCR), also known as congenital megacolon or intestinal aganglionosis. HSCR occurs in 1/5000 live births and typically presents with the inability to pass meconium, along with abdominal distension and discomfort that usually requires surgical resection of the aganglionic bowel. This disorder is characterized by a congenital absence of neurons in a portion of the intestinal tract, usually the distal colon, because of a disruption of normal neural crest cell migration, proliferation, differentiation, survival, and/or apoptosis. The inheritance of HSCR disease is complex, often non-Mendelian, and characterized by variable penetrance. Extensive research has identified a number of key genes that regulate neural crest cell development in the pathogenesis of HSCR including RET, GDNF, GFRα1, NRTN, EDNRB, ET3, ZFHX1B, PHOX2b, SOX10, and SHH. However, mutations in these genes account for only ∼50% of the known cases of HSCR. Thus, other genetic mutations and combinations of genetic mutations and modifiers likely contribute to the etiology and pathogenesis of HSCR. The aims of this review are to summarize the HSCR phenotype, diagnosis, and treatment options; to discuss the major genetic causes and the mechanisms by which they disrupt normal enteric neural crest cell development; and to explore new pathways that may contribute to HSCR pathogenesis.
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Hotta R, Anderson RB, Kobayashi K, Newgreen DF, Young HM. Effects of tissue age, presence of neurones and endothelin-3 on the ability of enteric neurone precursors to colonize recipient gut: implications for cell-based therapies. Neurogastroenterol Motil 2010; 22:331-e86. [PMID: 19775251 DOI: 10.1111/j.1365-2982.2009.01411.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Most enteric neurones arise from neural crest cells that originate in the post-otic hindbrain, and migrate into and along the developing gastrointestinal tract. There is currently great interest in the possibility of cell therapy to replace diseased or absent enteric neurones in patients with enteric neuropathies, such as Hirschsprung's disease. However, it is unclear whether neural crest stem/progenitor cells will be able to colonize colon (i) in which the mesenchyme has differentiated into distinct layers, (ii) that already contains enteric neurones or (iii) that lacks a gene expressed by the gut mesenchyme, such as endothelin-3 (Et-3). METHODS Co-cultures were used to examine the ability of enteric neural crest-derived cells (ENCCs) from E11.5 mouse gut to colonize a variety of recipient hindguts. KEY RESULTS Enteric neural crest-derived cells migrated and gave rise to neurones in E14.5 and E16.5 aneural colon in which the external muscle layers had differentiated, but they did not migrate as far as in younger colon. There was no evidence of altered ENCC proliferation, cell death or neuronal differentiation in older recipient explants. Enteric neural crest-derived cells failed to enter most recipient E14.5 and E16.5 colon explants already containing enteric neurones, and the few that did showed very limited migration. Finally, ENCCs migrated a shorter distance and a higher proportion expressed the pan-neuronal marker, Hu, in recipient E11.5 Et-3(-/-) colon compared to wild-type recipient colon. CONCLUSIONS & INFERENCES Age and an absence of Et-3 from the recipient gut both significantly reduced but did not prevent ENCC migration, but the presence of neurones almost totally prevented ENCC migration.
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Affiliation(s)
- R Hotta
- Department of Anatomy & Cell Biology, University of Melbourne, Victoria, Australia
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Abstract
Hirschsprung's disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the lower digestive tract. Aganglionosis is attributed to a disorder of the enteric nervous system (ENS) whereby ganglion cells fail to innervate the lower gastrointestinal tract during embryonic development. HSCR is a complex disease that results from the interaction of several genes and manifests with low, sex-dependent penetrance and variability in the length of the aganglionic segment. The genetic complexity observed in HSCR can be conceptually understood in light of the molecular and cellular events that take place during the ENS development. DNA alterations in any of the genes involved in the ENS development may interfere with the colonization process, and represent a primary etiology for HSCR. This review will focus on the genes known to be involved in HSCR pathology, how they interact, and on how technology advances are being employed to uncover the pathological processes underlying this disease.
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Abstract
Gastrointestinal development is a complex process comprising folding of the endodermal layer to form the primitive gut tube, cell differentiation along its anteroposterior axis, the budding of the various organ primordia and development of derivative organs like the liver and pancreas and the colonisation of the gut with neuronal precursors. Genetic factors are increasingly recognised as playing a significant role in the disturbance of this developmental process which underlies congenital malformations and gastrointestinal disorders. Furthermore, genetic variation and its interaction with environmental influences play an important role in the pathogenesis of functional gastrointestinal disorders. In this review, we discuss the contribution of genetic variants, ranging from highly penetrant mutations and chromosomal abnormalities to genetic polymorphisms, to the pathogenesis of a number of structural and functional gastrointestinal disorders.
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Affiliation(s)
- Shirley Hodgson
- Professor of Cancer Genetics, St.George's, University of London, United Kingdom
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Matera I, Cockroft JL, Moran JL, Beier DR, Goldowitz D, Pavan WJ. A mouse model of Waardenburg syndrome type IV resulting from an ENU-induced mutation in endothelin 3. ACTA ACUST UNITED AC 2007; 20:210-5. [PMID: 17516928 DOI: 10.1111/j.1600-0749.2007.00371.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
A line of mutant mice (114-CH19) exhibiting white spotting and preweaning lethality was identified during an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. The trait segregated as a semidominant bellyspot with reduced penetrance. Homozygous mutant mice showed preweaning lethality, and exhibited white spotting over the majority of the body surface, with pigmented patches remaining around the pinnae, eyes and tail. Linkage analysis localized 114-CH19 on mouse chromosome 2, suggesting endothelin 3 (Edn3) as a candidate gene. Sequence analysis of Edn3 identified a G > A transversion that encodes an arginine to histidine substitution (R96H). This mutation is predicted to disrupt furin-mediated proteolytic cleavage of pro-endothelin that is necessary to form biologically active EDN3. This mutation is novel among human and mouse EDN3 mutants, is the first reported EDN3 ENU mutant, and is the second reported EDN3 point mutation. This study demonstrates the power of using ENU mutagenesis screens to generate new animal models of human disease, and expands the spectrum of EDN3 mutant alleles.
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Affiliation(s)
- Ivana Matera
- Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20855, USA
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Tou JF, Li MJ, Guan T, Li JC, Zhu XK, Feng ZG. Mutation of RET proto-oncogene in Hirschsprung’s disease and intestinal neuronal dysplasia. World J Gastroenterol 2006; 12:1136-9. [PMID: 16534860 PMCID: PMC4087911 DOI: 10.3748/wjg.v12.i7.1136] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the genetic relationship between Hirschsprung’s disease (HD) and intestinal neuronal dysplasia (IND) in Chinese population.
METHODS: Peripheral blood samples were obtained from 30 HD patients, 20 IND patients, 18 HD/IND combined patients and 20 normal individuals as control. Genomic DNA was extracted according to standard procedure. Exons 11,13,15,17 of RET proto-oncogene were amplified by polymerase chain reaction (PCR). The mutations of RET proto-oncogene were analyzed by single strand conformational polymorphism (SSCP) and sequencing of the positive amplified products was performed.
RESULTS: Eight germline sequence variants were detected. In HD patients, 2 missense mutations in exon 11 at nucleotide 15165 G→A (G667S), 2 frameshift mutations in exon 13 at nucleotide 18974 (18974insG), 1 missense mutation in exon 13 at nucleotide 18919 A→G (K756E) and 1 silent mutation in exon 15 at nucleotide 20692 G→A(Q916Q) were detected. In HD/IND combined patients, 1 missense mutation in exon 11 at nucleotide 15165 G→A and 1 silent mutation in exon 13 at nucleotide 18888 T→G (L745L) were detected. No mutation was found in IND patients and controls.
CONCLUSION: Mutation of RET proto-oncogene is involved in the etiopathogenesis of HD. The frequency of RET proto-oncogene mutation is quite different between IND and HD in Chinese population. IND is a distinct clinical entity genetically different from HD.
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Affiliation(s)
- Jin-Fa Tou
- Department of Pediatric Surgery, Children's Hospital, Medical College of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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Affiliation(s)
- Paul K H Tam
- Department of Surgery and Genome Research Centre, The University of Hong Kong, Queen Mary Hospital K15, Pokfulam, Hong Kong, P.R. China.
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Abstract
AIM: To investigate the mutation of EDNRB gene and EDN-3 gene in sporadic Hirschsprung’s disease (HD) in Chinese population.
METHODS: Genomic DNA was extracted from bowel tissues of 34 unrelated HD patients which were removed by surgery. Exon 3, 4, 6 of EDNRB gene and Exon 1, 2 of EDN-3 gene were amplified by polymerase chain reaction (PCR) and analyzed by single strand conformation polymorphism (SSCP).
RESULTS: EDNRB mutations were detected in 2 of the 13 short-segment HD. One mutant was in the exon 3, the other was in the exon 6. EDN-3 mutation was detected in one of the 13 short-segment HD and in the exon 2. Both EDNRB and EDN-3 mutations were detected in one short-segment HD. No mutations were detected in the ordinary or long-segment HD.
CONCLUSION: The mutations of EDNRB gene and EDN-3 gene are found in the short-segment HD of sporadic Hirschsprung’s disease in Chinese population, which suggests that the EDNRB gene and EDN-3 gene play important roles in the pathogenesis of HD.
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Affiliation(s)
- Xiang-Long Duan
- Department of General Surgery, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Simonds WF. G Protein-Regulated Signaling Dysfunction in Human Disease. J Investig Med 2003. [DOI: 10.1177/108155890305100421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- William F. Simonds
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, Maryland
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Abstract
This review, which is presented in two parts, summarizes and synthesizes current views on the genetic, molecular, and cell biological underpinnings of the early embryonic phases of enteric nervous system (ENS) formation and its defects. In the first part, we describe the critical features of two principal abnormalities of ENS development: Hirschsprung's disease (HSCR) and intestinal neuronal dysplasia type B (INDB) in humans, and the similar abnormalities in animals. These represent the extremes of the diagnostic spectrum: HSCR has agreed and unequivocal diagnostic criteria, whereas the diagnosis and even existence of INDB as a clinical entity is highly controversial. The difficulties in diagnosis and treatment of both these conditions are discussed. We then review the genes now known which, when mutated or deleted, may cause defects of ENS development. Many of these genetic abnormalities in animal models give a phenotype similar or identical to HSCR, and were discovered by studies of humans and of mouse mutants with similar defects. The most important of these genes are those coding for molecules in the GDNF intercellular signaling system, and those coding for molecules in the ET-3 signaling system. However, a range of other genes for different signaling systems and for transcription factors also disturb ENS formation when they are deleted or mutated. In addition, a large proportion of HSCR cases have not been ascribed to the currently known genes, suggesting that additional genes for ENS development await discovery.
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Affiliation(s)
- Donald Newgreen
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, 3052, Victoria, Australia
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Abstract
Development of the ENS requires the function of a diverse set of genes encoding transcription factors, signaling molecules, and their receptors. Mutations of these genes result in altered ENS function in animals and humans. In particular, such mutations have been shown to contribute to many cases of Hirschsprung's disease. Elucidation of the mechanisms of ENS development and function allow the development of new approaches to the diagnosis, therapy, and prevention of human disorders of gastrointestinal motility.
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Affiliation(s)
- Michael D Bates
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio, USA.
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Abstract
Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder of neural crest migration. It has a strong genetic basis, although simple Mendelian inheritance is rarely observed. Hirschsprung disease is associated with several other anomalies and syndromes, and animal models for these conditions exist. Mutations in the RET gene are responsible for approximately half of familial cases and a smaller fraction of sporadic cases. Mutations in genes that encode RET ligands (GDNF and NTN); components of another signaling pathway (EDNRB, EDN3, ECE-1); and the transcription factor, SOX10, have been identified in HSCR patients. A subset of these mutations is associated with anomalies of pigmentation and/or hearing loss. For almost every HSCR gene, incomplete penetrance of the HSCR phenotype has been observed, probably due to genetic modifier loci. Thus, HSCR has become a model of a complex polygenic disorder in which the interplay of different genes is currently being elucidated.
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Affiliation(s)
- M A Parisi
- Department of Pediatrics, Children's Hospital and Regional Medical Center, Seattle, Washington, USA
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Kenny SE, Hofstra RM, Buys CH, Vaillant CR, Lloyd DA, Edgar DH. Reduced endothelin-3 expression in sporadic Hirschsprung disease. Br J Surg 2000; 87:580-5. [PMID: 10792313 DOI: 10.1046/j.1365-2168.2000.01401.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Enteric aganglionosis in Hirschsprung disease has been linked to genes coding for endothelin-3 (EDN3) and the endothelin B receptor (EDNRB), but there is no such linkage in most patients with sporadic Hirschsprung disease. However, the similarity between the distal colonic aganglionosis in Hirschsprung disease and that due to EDN3 or EDNRB mutations led to the hypothesis that levels of expression of these genes might be affected in the absence of mutation, thus causing the Hirschsprung disease phenotype. The aim of this study was to determine EDN3 and EDNRB messenger RNA (mRNA) levels in tissue samples from patients with sporadic Hirschsprung disease. METHODS RNA and DNA were isolated from the ganglionic and aganglionic colonic segments of ten children with sporadic Hirschsprung disease, and from the colon of ten age-matched controls. The DNA was analysed for mutations in the genes coding for endothelin-3 (ET-3) and endothelin B receptor (ET-B) proteins. Relative levels of EDN3 and EDNRB mRNA were determined by semi-quantitative transcriptase-polymerase chain reaction. RESULTS Three children had sequence variants in EDN3 and EDNRB. In the remaining seven patients, EDN3 mRNA levels were reduced in both the ganglionic and aganglionic colon compared with levels in controls; there was no difference in expression of EDNRB between groups. CONCLUSION In the absence of mutation, EDN3 is downregulated in short-segment Hirschsprung disease, suggesting that this may be a common step leading to aganglionosis.
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Affiliation(s)
- S E Kenny
- Departments of Child Health, Preclinical Veterinary Sciences, and Human Anatomy and Cell Biology, University of Liverpool, Liverpool, UK
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