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Neurocristopathy

About: Neurocristopathy is a research topic. Over the lifetime, 212 publications have been published within this topic receiving 9400 citations.


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Journal ArticleDOI
TL;DR: Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment, which stands as a model for genetic disorders with complex patterns of inheritance.
Abstract: Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.

1,109 citations

Journal ArticleDOI
TL;DR: An essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the autonomic nervous system in humans is supported.
Abstract: Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.

775 citations

Journal ArticleDOI
TL;DR: It is shown that patients from four families with WS4 have mutations in SOx10, whereas no mutation could be detected in patients with HSCR alone, and this point to an essential role ofSOx10 in the development of two neural crest-derived human cell lineages.
Abstract: Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest. WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls). The sl and ls phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively. The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOX10 in neural crest defects. Here we show that patients from four families with WS4 have mutations in SOX10, whereas no mutation could be detected in patients with HSCR alone. These mutations are likely to result in haploinsufficiency of the SOX10 product. Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOX10 in the development of two neural crest-derived human cell lineages.

773 citations

Journal ArticleDOI
TL;DR: It is determined that premature termination of SOX10, a member of the SflV–like HMG box family of transcription factors, is responsible for absence of the neural crest derivatives in Dom mice, andSOX10 is proposed as a candidate disease gene for individuals with HSCR whose disease does not have an identified genetic origin.
Abstract: Hirschsprung disease (HSCR, MIM #142623) is a multigenic neurocristopathy (neural crest disorder) characterized by absence of enteric ganglia in a variable portion of the distal colon. Subsets of HSCR individuals also present with neural crest-derived melanocyte deficiencies (Hirschsprung-Waardenburg, HSCR-WS, MIM #277580). Murine models have been instrumental in the identification and analysis of HSCR disease genes. These include mice with deficiencies of endothelin B receptor (Ednrb(s-l); refs 1,2) endothelin 3 (Edn3(ls): refs 1,3) the tyrosine kinase receptor cRet and glial-derived neurotrophic factor. Another mouse model of HSCR disease, Dom, arose spontaneously at the Jackson Laboratory. While Dom/+ heterozygous mice display regional deficiencies of neural crest-derived enteric ganglia in the distal colon, Dom/Dom homozygous animals are embryonic lethal. We have determined that premature termination of Sox10, a member of the SRY-like HMG box family of transcription factors, is responsible for absence of the neural crest derivatives in Dom mice. We demonstrate expression of Sox10 in normal neural crest cells, disrupted expression of both Sox10 and the HSCR disease gene Ednrb in Dom mutant embryos, and loss of neural crest derivatives due to apoptosis. Our studies suggest that Sox10 is essential for proper peripheral nervous system development. We propose SOX10 as a candidate disease gene for individuals with HSCR whose disease does not have an identified genetic origin.

708 citations

Journal ArticleDOI
TL;DR: Pheochromocytomas, neuroblastoma, neurofibromatosis, medullary carcinoma of the thyroid, carcinoid tumors, Hirschsprung's disease, and nonchromaffin paragangliomas are discussed and analysed in terms of their proposed neural crest origins.

578 citations

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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20218
20206
20194
20186
20178
20166