Genetic basis of Hirschsprung’s disease

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.

[1]  S. Morrison,et al.  Temporally Distinct Requirements for Endothelin Receptor B in the Generation and Migration of Gut Neural Crest Stem Cells , 2003, Neuron.

[2]  G. Romeo,et al.  Prevalence and Parental Origin of de novo RET Mutations in Hirschsprung’s Disease , 1996, European journal of human genetics : EJHG.

[3]  K. Lee,et al.  Prokineticin-1 modulates proliferation and differentiation of enteric neural crest cells. , 2007, Biochimica et biophysica acta.

[4]  J. Epstein,et al.  Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret. , 2000, The Journal of clinical investigation.

[5]  A. Munnich,et al.  A duplication in the L1CAM gene associated with X–linked hydrocephalus , 1993, Nature Genetics.

[6]  D. Lloyd,et al.  Expression of endothelin 3 by mesenchymal cells of embryonic mouse caecum , 1999, Gut.

[7]  J. Lupski,et al.  Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation , 1999, Annals of neurology.

[8]  C. Eng,et al.  RET mutations in multiple endocrine neoplasia type 2 and Hirschsprung disease , 1995, Current opinion in pediatrics.

[9]  J. Lupski,et al.  Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg–Hirschsprung disease: Phenotypes linked by SOX10 mutation , 2002, Annals of neurology.

[10]  P. Tam,et al.  Is there a role for the IHH gene in Hirschsprung's disease? , 2003, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[11]  J. Milbrandt,et al.  GFRα1-Deficient Mice Have Deficits in the Enteric Nervous System and Kidneys , 1998, Neuron.

[12]  M. Ichihara,et al.  Functional analysis of RET with Hirschsprung mutations affecting its kinase domain. , 2001, Gastroenterology.

[13]  Kevin M. Bradley,et al.  Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease. , 2004, Human molecular genetics.

[14]  N. Asai,et al.  Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain. , 1996, Human molecular genetics.

[15]  A. Munnich,et al.  Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease , 1996, Nature Genetics.

[16]  L. Mulligan,et al.  De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. , 1996, Human molecular genetics.

[17]  W. Pavan,et al.  SOX10 mutation disrupts neural crest development in Dom Hirschsprung mouse model , 1998, Nature Genetics.

[18]  A. Chakravarti,et al.  Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient , 1996, Nature Genetics.

[19]  P. Tam,et al.  Evaluation of the Thyroid Transcription Factor‐1 Gene (TITF1) as a Hirschsprung's Disease Locus , 2007, Annals of human genetics.

[20]  L. Garavelli,et al.  Hirschsprung disease, mental retardation, characteristic facial features, and mutation in the gene ZFHX1B (SIP1): Confirmation of the Mowat‐Wilson syndrome , 2003, American journal of medical genetics. Part A.

[21]  P. Puri,et al.  Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease. , 1996, Human molecular genetics.

[22]  B. Pasini,et al.  Heterogeneity and Low Detection Rate of RET Mutations in Hirschsprung Disease , 1994, European journal of human genetics : EJHG.

[23]  A. Rosenthal,et al.  Hedgehog signal transduction: from flies to vertebrates. , 1999, Experimental cell research.

[24]  A. Ballabio,et al.  Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. , 1996, Human molecular genetics.

[25]  P. Tam,et al.  Analysis of SOX10 mutations identified in Waardenburg‐Hirschsprung patients: Differential effects on target gene regulation , 2003, Journal of cellular biochemistry.

[26]  V. Jasonni,et al.  Ret protein in the human fetal rectum. , 1996, Journal of pediatric surgery.

[27]  C. Lacroix,et al.  Peripheral neuropathy with hypomyelination, chronic intestinal pseudo‐obstruction and deafness: A developmental “neural crest syndrome” related to a SOX10 mutation , 2000, Annals of neurology.

[28]  J. Osinga,et al.  A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. , 1999, American journal of human genetics.

[29]  R. Hofstra,et al.  Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease? , 2002, American journal of medical genetics.

[30]  Dietmar Roesner,et al.  Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease , 2002, The Lancet.

[31]  L. Mulligan,et al.  Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. , 1994, Human molecular genetics.

[32]  A. Munnich,et al.  Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome , 2003, Nature Genetics.

[33]  B. Kerr,et al.  Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. , 1998, Journal of medical genetics.

[34]  Jicheng Li,et al.  Mutation of RET gene in Chinese patients with Hirschsprung's disease. , 2002, World journal of gastroenterology.

[35]  R. Hofstra,et al.  A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma , 1994, Nature.

[36]  J. Epstein,et al.  Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer. , 2003, Human molecular genetics.

[37]  I. Verma,et al.  SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism , 2002, Human Genetics.

[38]  P. Tam,et al.  Molecular genetics of Hirschsprung's disease. , 2004, Seminars in pediatric surgery.

[39]  X. Miao,et al.  Correlation Between Genetic Variations in Hox Clusters and Hirschsprung's Disease , 2007, Annals of human genetics.

[40]  F. Wright,et al.  A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung disease and a subset of cases of sporadic medullary thyroid carcinoma. , 2003, American journal of human genetics.

[41]  A. Puliti,et al.  Human homology and candidate genes for the Dominant megacolon locus, a mouse model of Hirschsprung disease. , 1997, Genomics.

[42]  A. Munnich,et al.  Endothelin-3 Gene Mutations in Isolated and Syndromic Hirschsprung Disease , 1997, European journal of human genetics : EJHG.

[43]  Isabelle Janoueix-Lerosey,et al.  Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. , 2005, Cancer letters.

[44]  J. Louis,et al.  GDNF–Induced Activation of the Ret Protein Tyrosine Kinase Is Mediated by GDNFR-α, a Novel Receptor for GDNF , 1996, Cell.

[45]  I. König,et al.  Compound effect of PHOX2B and RET gene variants in congenital central hypoventilation syndrome combined with Hirschsprung disease , 2008, American journal of medical genetics. Part A.

[46]  B. Pasini,et al.  Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease , 1994, Nature.

[47]  S. Moore.  The contribution of associated congenital anomalies in understanding Hirschsprung’s disease , 2006, Pediatric Surgery International.

[48]  P. Tam,et al.  Glial Cell Line–Derived Neurotrophic Factor Family Receptors Are Abnormally Expressed in Aganglionic Bowel of a Subpopulation of Patients with Hirschsprung's Disease , 2002, Laboratory Investigation.

[49]  M. Santoro,et al.  Molecular Cloning of PTC, a New Oncogene Found Activated in Human Thyroid Papillary Carcinomas and Their Lymph Node Metastases a , 1988, Annals of the New York Academy of Sciences.

[50]  R. Agarwala,et al.  The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. , 1999, Genome research.

[51]  T. Matise,et al.  Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. , 1994, Human molecular genetics.

[52]  C. Goridis,et al.  The Phox2b transcription factor coordinately regulates neuronal cell cycle exit and identity. , 2000, Development.

[53]  P. Anand,et al.  Idiopathic slow transit constipation and megacolon are not associated with neurturin mutations , 2002, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[54]  A. Munnich,et al.  Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome) , 1996, Nature Genetics.

[55]  P. Tam,et al.  Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. , 1996, Human molecular genetics.

[56]  H. Lee,et al.  Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors , 2004, Nature Genetics.

[57]  J. Celli,et al.  Association of multiple endocrine neoplasia type 2 and Hirschsprung disease , 1998, Journal of internal medicine.

[58]  R. Ravazzolo,et al.  A rare haplotype of the RET proto-oncogene is a risk-modifying allele in hirschsprung disease. , 2002, American journal of human genetics.

[59]  S. Morrison,et al.  Hirschsprung Disease Is Linked to Defects in Neural Crest Stem Cell Function , 2003, Science.

[60]  P. Tam,et al.  Sonic hedgehog regulates the proliferation, differentiation, and migration of enteric neural crest cells in gut , 2004, The Journal of cell biology.

[61]  M. Garcia-Barceló,et al.  Association study of PHOX2B as a candidate gene for Hirschsprung’s disease , 2003, Gut.

[62]  G. Tonini,et al.  PHOX2B mutations and genetic predisposition to neuroblastoma , 2005, Oncogene.

[63]  V. D’Agati,et al.  RET‐deficient mice: an animal model for Hirschsprung's disease and renal agenesis , 1995, Journal of internal medicine.

[64]  A. Munnich,et al.  Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. , 1995, Human molecular genetics.

[65]  V. Pachnis,et al.  Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development. , 2006, Developmental biology.

[66]  You-Qiang Song,et al.  Chinese patients with sporadic Hirschsprung’s disease are predominantly represented by a single RET haplotype , 2003, Journal of medical genetics.

[67]  R. Ravazzolo,et al.  Hirschsprung associated GDNF mutations do not prevent RET activation , 2002, European Journal of Human Genetics.

[68]  C. Eng,et al.  Low frequency of RET mutations in Hirschsprung disease in Sweden , 1998, Clinical genetics.

[69]  F. Costantini,et al.  Expression of the c-ret proto-oncogene during mouse embryogenesis. , 1993, Development.

[70]  E. Grice,et al.  A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk , 2005, Nature.

[71]  M. Vekemans,et al.  PMX2B, a new candidate gene for Hirschsprung's disease , 2003, Clinical genetics.

[72]  P. Puri,et al.  Mutation analysis of the RET, the endothelin-B receptor, and the endothelin-3 genes in sporadic cases of Hirschsprung's disease. , 1997, Journal of pediatric surgery.

[73]  T. Shimotake,et al.  Mutational analysis of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease. , 1999, Journal of pediatric surgery.

[74]  Masashi Yanagisawa,et al.  A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease , 1994, Cell.

[75]  Y. Wada,et al.  Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM. , 1997, Journal of medical genetics.

[76]  M. Anvret,et al.  A Heterozygous Frameshift Mutation in the Endothelin-3 (EDN-3) Gene in Isolated Hirschsprung's Disease , 1999, Pediatric Research.

[77]  J. Weissenbach,et al.  A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10 , 1993, Nature Genetics.

[78]  R. Hennekam,et al.  A molecular analysis of the yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies. , 1999, Human molecular genetics.

[79]  R. Ravazzolo,et al.  Single nucleotide polymorphic alleles in the 5′ region of the RET proto-oncogene define a risk haplotype in Hirschsprung’s disease , 2003, Journal of medical genetics.

[80]  M. Schachner,et al.  Expression of neural cell adhesion molecule L1 during development, in neurological mutants and in the peripheral nervous system. , 1984, Brain research.

[81]  M. Yanagisawa,et al.  Novel Mutations of the Endothelin B Receptor Gene in Patients with Hirschsprung’s Disease and Their Characterization* , 1998, The Journal of Biological Chemistry.

[82]  G. D. Vita,et al.  Two distinct mutations of the RET receptor causing Hirschsprung's disease impair the binding of signalling effectors to a multifunctional docking site. , 1999, Human molecular genetics.

[83]  S. Huson,et al.  Hirschsprung's disease associated with a deletion of chromosome 10 (q11.2q21.2): a further link with the neurocristopathies? , 1994, Journal of medical genetics.

[84]  A. Sidow,et al.  Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[85]  A. Green,et al.  Mutation analysis of the RET gene in total intestinal aganglionosis by wave DNA fragment analysis system. , 2003, Journal of pediatric surgery.

[86]  A. von Deimling,et al.  Investigation of germline GFRα-1 mutations in Hirschsprung disease , 1999 .

[87]  D. Melton,et al.  Hedgehog signals regulate multiple aspects of gastrointestinal development. , 2000, Development.

[88]  B. Lu,et al.  Gdnf haploinsufficiency causes Hirschsprung-like intestinal obstruction and early-onset lethality in mice. , 2002, American journal of human genetics.

[89]  J. Osinga,et al.  ABCD syndrome is caused by a homozygous mutation in the EDNRB gene. , 2002, American journal of medical genetics.

[90]  R. Ravazzolo,et al.  Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. , 2005, Human molecular genetics.

[91]  G. Raisman,et al.  Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system. , 1999, Development.

[92]  K. Bär,et al.  Glial-derived neurotrophic factor in human adult and fetal intestine and in Hirschsprung's disease. , 1997, Gastroenterology.

[93]  M. Wegner,et al.  Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[94]  P. Puri,et al.  Mutations of the endothelin-B receptor and endothelin-3 genes in Hirschsprung's disease , 2005, Pediatric Surgery International.

[95]  R. Hammer,et al.  Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. , 1998, Development.

[96]  P. Tam,et al.  Normalization and analysis of cDNA microarrays using within-array replications applied to neuroblastoma cell response to a cytokine. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[97]  M. Santoro,et al.  PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas , 1990, Cell.

[98]  M. Yanagisawa,et al.  Functional analysis of five endothelin-B receptor mutations found in human Hirschsprung disease patients. , 2000, Biochemical and biophysical research communications.

[99]  A. Chakravarti,et al.  A genetic study of Hirschsprung disease. , 1990, American journal of human genetics.

[100]  P. Goodfellow,et al.  Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. , 1993, Human molecular genetics.

[101]  H. Schackert,et al.  Association of RET protooncogene codon 45 polymorphism with Hirschsprung disease. , 1999, American journal of human genetics.

[102]  X. Morin,et al.  The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives , 1999, Nature.

[103]  Carel Meijers,et al.  Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems. , 2005, American journal of human genetics.

[104]  R. A. Decker,et al.  Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease. , 1995, Surgery.

[105]  X. Miao,et al.  Perturbation of hoxb5 signaling in vagal neural crests down-regulates ret leading to intestinal hypoganglionosis in mice. , 2008, Gastroenterology.

[106]  P. Sham,et al.  Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease , 2009, Proceedings of the National Academy of Sciences.

[107]  Carel Meijers,et al.  A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome) , 1996, Nature Genetics.

[108]  J. Osinga,et al.  RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems , 2000, Human mutation.

[109]  T. Matise,et al.  A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 , 1993, Nature Genetics.

[110]  Dietmar Roesner,et al.  Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR). , 2003, Human molecular genetics.

[111]  A. Buj-Bello,et al.  Characterization of a multicomponent receptor for GDNF , 1996, Nature.

[112]  A. Chakravarti,et al.  Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. , 1995, Human molecular genetics.

[113]  C. Gariepy.  Intestinal Motility Disorders and Development of the Enteric Nervous System , 2001, Pediatric Research.

[114]  B. Ponder,et al.  Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A , 1993, Nature.

[115]  A. Ballabio,et al.  Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. , 1999, American journal of human genetics.

[116]  A. von Deimling,et al.  Investigation of germline GFR alpha-1 mutations in Hirschsprung disease. , 1999, Journal of medical genetics.

[117]  I. Fariñas,et al.  Renal and neuronal abnormalities in mice lacking GDNF , 1996, Nature.

[118]  N. Nomura,et al.  Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease , 2001, Nature Genetics.

[119]  G. Mortier,et al.  Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. , 2003, American journal of human genetics.

[120]  Minerva M. Carrasquillo,et al.  Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease , 2002, Nature Genetics.

[121]  F. Pinet,et al.  Functional Characterization of Three Mutations of the Endothelin B Receptor Gene in Patients With Hirschsprung’s Disease: Evidence for Selective Loss of Gi Coupling , 2001, Molecular medicine.

[122]  P. Tam,et al.  Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease. , 2004, Clinical chemistry.

[123]  W. Bodmer,et al.  Common and rare variants in multifactorial susceptibility to common diseases , 2008, Nature Genetics.

[124]  O. Swenson.  Early history of the therapy of Hirschsprung's disease: facts and personal observations over 50 years. , 1996, Journal of pediatric surgery.

[125]  T. Shimotake,et al.  Mutational analysis of RET/GDNF/NTN genes in children with total colonic aganglionosis with small bowel involvement. , 2000, American journal of medical genetics.

[126]  M. Cosma,et al.  A mutation in the RET proto-oncogene in Hirschsprung's disease affects the tyrosine kinase activity associated with multiple endocrine neoplasia type 2A and 2B. , 1996, The Biochemical journal.

[127]  M. Fu,et al.  HOXB5 expression is spatially and temporarily regulated in human embryonic gut during neural crest cell colonization and differentiation of enteric neuroblasts , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[128]  G. Gimelli,et al.  Total colonic aganglionosis associated with interstitial deletion of the long arm of chromosome 10 , 1992, Pediatric Surgery International.

[129]  A. Munnich,et al.  Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease. , 1998, The Journal of clinical investigation.

[130]  K. Kidd,et al.  Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage , 1987, Nature.

[131]  L. Mulligan,et al.  Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus. , 1994, Journal of medical genetics.

[132]  R. Hammer,et al.  Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons , 1994, Cell.

[133]  R. Hofstra,et al.  DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the ret proto-oncogene. , 1995, Oncogene.

[134]  M. Santoro,et al.  The oncogene associated with human papillary thyroid carcinoma (PTC) is assigned to chromosome 10 q11-q12 in the same region as multiple endocrine neoplasia type 2A (MEN2A). , 1989, Oncogene.

[135]  A. McCallion,et al.  EDNRB/EDN3 and Hirschsprung disease type II. , 2001, Pigment cell research.

[136]  Xinping Yang,et al.  Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1 , 2001, Nature Genetics.

[137]  Mart Saarma,et al.  The GDNF family: Signalling, biological functions and therapeutic value , 2002, Nature Reviews Neuroscience.

[138]  J. Osinga,et al.  Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2 , 2004, European Journal of Human Genetics.

[139]  Aravinda Chakravarti,et al.  Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue-specific interaction between Ret and Ednrb , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[140]  S. Moore,et al.  Novel RET mutations in Hirschsprung's disease patients from the diverse South African population , 2001, European Journal of Human Genetics.

[141]  A. Munnich,et al.  Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. , 1998, Human molecular genetics.

[142]  V. Pachnis,et al.  Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis. , 2002, Development.

[143]  S. Eketjäll,et al.  Functional characterization of mutations in the GDNF gene of patients with Hirschsprung disease. , 2002, Human molecular genetics.

[144]  A. von Deimling,et al.  Analysis of the RET,GDNF, EDN3, andEDNRB genes in patients with intestinal neuronal dysplasia and Hirschsprung disease , 2001, Gut.

[145]  S. Borrego,et al.  RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease , 2000, Journal of medical genetics.

[146]  P. Sham,et al.  Mapping of a Hirschsprung's disease locus in 3p21 , 2008, European Journal of Human Genetics.

[147]  R. Hofstra,et al.  Oncological implications of RET gene mutations in Hirschsprung’s disease , 1998, Gut.

[148]  A. Munnich,et al.  Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. , 2000, American journal of human genetics.

[149]  M. Ruíz-Ferrer,et al.  A Novel Point Variant in NTRK3, R645C, Suggests a Role of this Gene in the Pathogenesis of Hirschsprung Disease , 2009, Annals of human genetics.

[150]  M. Borrello,et al.  Loss of function effect of RET mutations causing Hirschsprung disease , 1995, Nature Genetics.

[151]  A. Burns,et al.  The sacral neural crest contributes neurons and glia to the post-umbilical gut: spatiotemporal analysis of the development of the enteric nervous system. , 1998, Development.

[152]  D. Lloyd,et al.  Localization and endothelin-3 dependence of stem cells of the enteric nervous system in the embryonic colon. , 2002, Journal of pediatric surgery.

[153]  Giovanni Romeo,et al.  SOX10 mutations in patients with Waardenburg-Hirschsprung disease , 1998, Nature Genetics.

[154]  Misha Angrist,et al.  Segregation at three loci explains familial and population risk in Hirschsprung disease , 2002, Nature Genetics.

[155]  J. Osinga,et al.  Hirschsprung disease and L1CAM: is the disturbed sex ratio caused by L1CAM mutations? , 2002, Journal of medical genetics.

[156]  B. Pasini,et al.  Frequency of RET mutations in long‐ and short‐segment Hirschsprung disease , 1997, Human mutation.

[157]  J. Osinga,et al.  Identifying candidate Hirschsprung disease-associated RET variants. , 2005, American journal of human genetics.

[158]  P. Lane,et al.  Association of megacolon with a new dominant spotting gene (Dom) in the mouse. , 1984, The Journal of heredity.

[159]  E. Graaff,et al.  Enteric Nervous System Progenitors Are Coordinately Controlled by the G Protein-Coupled Receptor EDNRB and the Receptor Tyrosine Kinase RET , 2003, Neuron.

[160]  P. Sham,et al.  TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease. , 2005, Human molecular genetics.

[161]  R. Hammer,et al.  Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice , 1994, Cell.

[162]  B. Ponder,et al.  Mutations of the RET proto-oncogene in Hirschsprung's disease , 1994, Nature.

[163]  P. Tam,et al.  Novel mutations of SOX10 suggest a dominant negative role in Waardenburg-Shah syndrome , 2001, Journal of medical genetics.

[164]  P. Tam,et al.  Role of RET and ko=PHOX2B gene polymorphisms in risk of Hirschsprung’s disease in Chinese population , 2007, Gut.

[165]  M. Daly,et al.  Genetic Mapping in Human Disease , 2008, Science.

[166]  S. Borrego,et al.  Specific polymorphisms in the RETproto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression , 1999, Journal of medical genetics.

[167]  A. Chakravarti,et al.  A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[168]  A. Rauch,et al.  Mowat–Wilson syndrome and mutation in the zinc finger homeo box 1B gene: a well defined clinical entity , 2004, Journal of Medical Genetics.

[169]  A. Munnich,et al.  Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. , 1995, Human molecular genetics.

[170]  J. Milbrandt,et al.  GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys. , 1998, Neuron.

[171]  A Chakravarti,et al.  Hirschsprung disease, associated syndromes and genetics: a review , 2001, Journal of Medical Genetics.

[172]  L. Mulligan,et al.  De Novo Mutation of GDNF, Ligand for the RET/GDNFR-α Receptor Complex, in Hirschsprung Disease , 1996 .

[173]  A. Verloes,et al.  Ondine-Hirschsprung syndrome (Haddad syndrome). Further delineation in two cases and review of the literature. , 1993, European journal of pediatrics.

[174]  A. Wakizaka,et al.  Japanese patients with sporadic Hirschsprung: mutation analysis of the receptor tyrosine kinase proto-oncogene, endothelin-B receptor, endothelin-3, glial cell line-derived neurotrophic factor and neurturin genes: a comparison with similar studies , 2000, European Journal of Pediatrics.

[175]  P. Tam,et al.  Incidence of RET mutations in patients with Hirschsprung's disease. , 2000, Journal of pediatric surgery.