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Anna Pelet - One of the best experts on this subject based on the ideXlab platform.
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Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease.
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Loïc De Pontual, Norann A Zaghloul, Sophie Thomas, Erica E Davis, David M Mcgaughey, Hélène Dollfus, Clarisse Baumann, Seneca L Bessling, Candice Babarit, Anna PeletAbstract:Hirschsprung disease (HSCR) is a common, multigenic Neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.
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neurological phenotype in waardenburg syndrome type 4 correlates with novel sox10 truncating mutations and expression in developing brain
American Journal of Human Genetics, 2000Co-Authors: Renaud Touraine, Anna Pelet, Veronique Pingault, Tania Attiebitach, Eric Manceau, Eckhard Korsch, Pierre Sarda, Ferechte Encharazavi, Joelle Auge, Annie NivelonchevallierAbstract:Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare Neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S351X in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest–derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest–derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system.
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molecular genetics of hirschsprung disease a model of multigenic Neurocristopathy
Biologie Aujourd'hui, 2000Co-Authors: Jeanne Amiel, Anna Pelet, Remi Salomon, Arnold Munnich, C Nihoulfekete, Renaud Touraine, Tania Attiebitach, Julie Steffann, Michel Vekemans, Stanislas LyonnetAbstract:Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic Neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB an EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.
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endothelin 3 gene mutations in isolated and syndromic hirschsprung disease
European Journal of Human Genetics, 1997Co-Authors: Christelle Bidaud, Tawab Attie, Anna Pelet, G. Van Camp, Patrick J. Willems, Maryse Bonduelle, Remi Salomon, Jeanne Amiel, C Nihoulfekete, Arnold MunnichAbstract:Abstract Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic Neurocristopathy. Four susceptibility genes have recently been identified in HSCR, namely the RET proto-oncogene, the glial cell line-derived neurotrophic factor (GDNF), the endothelin B receptor (EDNRB) and the endothelin-3 genes (EDN3). Homozygosity for EDN3 mutations has been previously shown to cause the Shah-Waardenburg syndrome, a combination of HSCR with features of the Waardenburg syndrome. Here, we report on heterozygous EDN3 missense mutations in isolatec HSCR. The present data give further support to the role of the endothelin signaling pathway in the development of neural crest-derived enteric neurons. They also suggest the possibility that either recessive or weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.
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heterozygous endothelin receptor b ednrb mutations in isolated hirschsprung disease
Human Molecular Genetics, 1996Co-Authors: Jeanne Amiel, Christelle Bidaud, Tawab Attie, Anna Pelet, Dominique Jan, Patrick Edery, Didier Lacombe, Paul K H Tam, Juliette Simeoni, Elisabeth FloriAbstract:Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic Neurocristopathy. Two susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association. Here, we report heterozygous EDNRB missense mutations (G57S, R319W and P383L) in isolated HSCR. These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features. In addition, the present data give further support to the role of the endothelin-signalling pathway in the development of neural crest-derived enteric neurons.
Veronique Pingault - One of the best experts on this subject based on the ideXlab platform.
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a novel mutation in the endothelin b receptor gene in a moroccan family with shah waardenburg syndrome
Molecular Syndromology, 2015Co-Authors: Yassamine Doubaj, Veronique Pingault, Siham Chafai Elalaoui, Ilham Ratbi, Mohamed Azouz, Hicham Zerhouni, F Ettayebi, Abdelaziz SefianiAbstract:Waardenburg syndrome (WS) is a Neurocristopathy disorder combining sensorineural deafness and pigmentary abnormalities. The presence of additional signs defines the 4 subtypes. WS type IV, also called Shah-Waardenburg syndrome (SWS), is characterized by the association with congenital aganglionic megacolon (Hirschsprung disease). To date, 3 causative genes have been related to this congenital disorder. Mutations in the EDNRB and EDN3 genes are responsible for the autosomal recessive form of SWS, whereas SOX10 mutations are inherited in an autosomal dominant manner. We report here the case of a 3-month-old Morrocan girl with WS type IV, born to consanguineous parents. The patient had 3 cousins who died in infancy with the same symptoms. Molecular analysis by Sanger sequencing revealed the presence of a novel homozygous missense mutation c.1133A>G (p.Asn378Ser) in the EDNRB gene. The proband's parents as well as the parents of the deceased cousins are heterozygous carriers of this likely pathogenic mutation. This molecular diagnosis allows us to provide genetic counseling to the family and eventually propose prenatal diagnosis to prevent recurrence of the disease in subsequent pregnancies.
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screening of mitf and sox10 regulatory regions in waardenburg syndrome type 2
PLOS ONE, 2012Co-Authors: Viviane Baral, Michel Goossens, Sandrine Marlin, Asma Chaoui, Yuli Watanabe, Tania Attiebitach, Veronique PingaultAbstract:Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this Neurocristopathy.
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neurological phenotype in waardenburg syndrome type 4 correlates with novel sox10 truncating mutations and expression in developing brain
American Journal of Human Genetics, 2000Co-Authors: Renaud Touraine, Anna Pelet, Veronique Pingault, Tania Attiebitach, Eric Manceau, Eckhard Korsch, Pierre Sarda, Ferechte Encharazavi, Joelle Auge, Annie NivelonchevallierAbstract:Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare Neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S351X in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest–derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest–derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system.
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a molecular analysis of the yemenite deaf blind hypopigmentation syndrome sox10 dysfunction causes different neurocristopathies
Human Molecular Genetics, 1999Co-Authors: Nadege Bondurand, Veronique Pingault, Kirsten Kuhlbrodt, Janna Enderich, Marc Sajus, Niels Tommerup, Mette Warburg, Raoul C M Hennekam, Andrew P Read, Michael WegnerAbstract:The Yemenite deaf-blind hypopigmentation syndrome was first observed in a Yemenite sister and brother showing cutaneous hypopigmented and hyperpigmented spots and patches, microcornea, coloboma and severe hearing loss. A second case, observed in a girl with similar skin symptoms and hearing loss but without microcornea or coloboma, was reported as a mild form of this syndrome. Here we show that a SOX10 missense mutation is responsible for the mild form, resulting in a loss of DNA binding of this transcription factor. In contrast, no SOX10 alteration could be found in the other, severe case of the Yemenite deaf-blind hypopigmentation syndrome. Based on genetic, clinical, molecular and functional data, we suggest that these two cases represent two different syndromes. Moreover, as mutations of the SOX10 transcription factor were previously described in Waardenburg-Hirschsprung disease, these results show that SOX10 mutations cause various types of Neurocristopathy.
Isabella Ceccherini - One of the best experts on this subject based on the ideXlab platform.
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desogestrel down regulates phox2b and its target genes in progesterone responsive neuroblastoma cells
Experimental Cell Research, 2018Co-Authors: Silvia Cardani, Simona Di Lascio, Debora Belperio, Roberta Benfante, Isabella Ceccherini, Erika Di Biase, Diego FornasariAbstract:The paired-like homeobox 2B gene (PHOX2B) encodes a key transcription factor that plays a role in the development of the autonomic nervous system and the neural structures involved in controlling breathing. In humans, PHOX2B over-expression plays a role in the pathogenesis of tumours arising from the sympathetic nervous system such as neuroblastomas, and heterozygous PHOX2B mutations cause Congenital Central Hypoventilation Syndrome (CCHS), a life-threatening Neurocristopathy characterised by the defective autonomic control of breathing and involving altered CO2/H+ chemosensitivity. The recovery of CO2/H+ chemosensitivity and increased ventilation have been observed in two CCHS patients using the potent contraceptive progestin desogestrel. Given the central role of PHOX2B in the pathogenesis of CCHS, and the progesterone-mediated effects observed in the disease, we generated progesterone-responsive neuroblastoma cells, and evaluated the effects of 3-Ketodesogestrel (3-KDG), the biologically active metabolite of desogestrel, on the expression of PHOX2B and its target genes. Our findings demonstrate that, through progesterone nuclear receptor PR-B, 3-KDG down-regulates PHOX2B gene expression, by a post-transcriptional mechanism, and its target genes and open up the possibility that this mechanism may contribute to the positive effects observed in some CCHS patients.
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structural and functional differences in phox2b frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome
Human Mutation, 2018Co-Authors: Simona Di Lascio, Diego Fornasari, Roberta Benfante, Isabella Ceccherini, Silvia Cardani, Eleonora Di Zanni, Annalisa Adamo, Tiziana BachettiAbstract:Heterozygous mutations in the PHOX2B gene are causative of Congenital Central Hypoventilation Syndrome (CCHS), a Neurocristopathy characterised by defective autonomic control of breathing due to the impaired differentiation of neural crest cells (NCCs). Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This paper provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published. These were considered in terms of both their structure, whether the underlying indels induced frameshifts of either 1 or 2 steps (“frame 2″ and “frame 3″ mutations respectively), and clinical associations. Furthermore, we evaluated the structural and functional effects of one “frame 3″ mutation identified in a patient with isolated CCHS, and one “frame 2″ mutation identified in a patient with syndromic CCHS, also affected with Hirschsprung's disease and neuroblastoma. The data thus obtained confirm that the type of translational frame affects the severity of the transcriptional dysfunction and the predisposition to isolated or syndromic CCHS. This article is protected by copyright. All rights reserved
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1 Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in Congenital Central Hypoventilation Syndrome
2016Co-Authors: Tiziana Bachetti, Ivana Matera, Silvia Borghini, Marco Di Duca, Isabella CeccheriniAbstract:g.oxfordjournals.org/ D ow nloaded from 2 Congenital Central Hypoventilation Syndrome (CCHS) is a rare Neurocristopathy characterized by absence of adequate autonomic control of respiration with decreased sensitivity to hypoxia and hypercapnia. Frameshift mutations and polyalanine triplet expansions in the coding region of PHOX2B have been identified in the vast majority of CCHS patients and a correlation between length of the expanded region and severity of CCHS has been reported. In this work we have undertaken in vitro analyses aimed at identifying the pathogenetic mechanisms which underlie the effects of PHOX2B mutations in CCHS. According to the known role of this gene, a transcription factor expressed during autonomic nervou
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low amounts of phox2b expanded alleles in asymptomatic parents suggest unsuspected recurrence risk in congenital central hypoventilation syndrome
Journal of Molecular Medicine, 2011Co-Authors: Tiziana Bachetti, Marco Di Duca, Sara Parodi, Giuseppe Santamaria, Roberto Ravazzolo, Isabella CeccheriniAbstract:Heterozygous trinucleotide in frame duplications, leading to expansions of variable lengths of a 20-alanine stretch (polyAla), is the most frequent PHOX2B variant associated with congenital central hypoventilation syndrome (CCHS), a rare Neurocristopathy characterized by defective response of the autonomic nervous system to hypoxia and hypercapnia. Sequencing analysis has shown that the vast majority of polyAla expansions arise de novo; while in about 10% of cases, mutations are inherited by one parent who carries either constitutive or somatic mutations. To investigate transmission of PHOX2B mutant alleles from asymptomatic individuals, we have reassessed 44 parental pairs, previously resulted not to carry any mutation, by coupling amplification with FAM-tagged primers and capillary electrophoresis. Low levels of somatic mosaicism were shown in five parents previously undetected, thus increasing the inherited occurrence of the disease from 10% to 25% of the cases. Analysis of the technical detection limits has confirmed a power of resolution much higher for the "FAM" protocol than for the "sequencing" method. These observations are going to have relevant implications on how the carrier status of asymptomatic parents should be assessed and on successive genetic counseling to CCHS families.
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parental origin and somatic mosaicism of phox2b mutations in congenital central hypoventilation syndrome
Human Mutation, 2008Co-Authors: Syndrome Parodi, Tiziana Bachetti, Ivana Matera, Marco Di Duca, Giancarlo Ottonello, Francesca Lantieri, Giuseppe Santamaria, Roberto Ravazzolo, Isabella CeccheriniAbstract:Heterozygous polyalanine repeat expansions of PHOX2B have been associated with Congenital Central Hypoventilation Syndrome, a rare Neurocristopathy characterized by absence of adequate control of respiration during sleep. Here we report a PHOX2B mutational screening in 63 CCHS patients, 58 of whom presenting with poly-A expansions or frameshift, missense and nonsense mutations. To assess a somatic or germline occurrence of poly-A length variations, the relative amounts of mutant and wild type alleles have been quantified in 20 selected CCHS patients presenting with an expansion, and in their parents. Somatic mosaicism was shown in four parents, while no mosaic was found among CCHS patients. Moreover, while co-segregation analysis of the PHOX2B poly-A expansions with selected marker alleles in the same 20 CCHS trios has not demonstrated any parent-of-origin effect of the mutations, it has provided further clues to clarify the molecular mechanism underlying the expansion occurrence. Finally, the segregation of PHOX2B poly-A anomalous tracts within family members has allowed us to exclude tendency of polymorphic variations towards expansion. This strengthens the notion that expanded polyalanine tracts, identified as frequent disease-causing mutations also in other human diseases, are mitotically and meiotically stable.
Jeanne Amiel - One of the best experts on this subject based on the ideXlab platform.
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Review article Hirschsprung disease, associated syndromes, and genetics: a review
2016Co-Authors: Jeanne Amiel, Stanislas LyonnetAbstract:Hirschsprung disease (HSCR, aganglionic megacolon) is the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This devel-opmental 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 dramatically decreased mortality and morbidity, which has allowed the emer-gence of familial cases. HSCR appeared to be a multifactorial malformation with low, sex dependent penetrance and vari-able expression according to the length of the aganglionic segment, suggesting the involvement of one or more gene(s) with low penetrance. So far, eight genes have been found to be involved in HSCR. This frequent congenital malformation now stands as a model for genetic disorders with complex patterns of inheritance
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autonomic Neurocristopathy associated mutations in phox2b dysregulate sox10 expression
Journal of Clinical Investigation, 2012Co-Authors: Mayumi Nagashimada, Jeanne Amiel, Jeanfrancois Brunet, Hiroshi Ohta, Kazuki Nakao, Toshihiro Uesaka, Teruhiko Wakayama, Hideki EnomotoAbstract:The most common forms of Neurocristopathy in the autonomic nervous system are Hirschsprung disease (HSCR), resulting in congenital loss of enteric ganglia, and neuroblastoma (NB), childhood tumors originating from the sympathetic ganglia and adrenal medulla. The risk for these diseases dramatically increases in patients with congenital central hypoventilation syndrome (CCHS) harboring a nonpolyalanine repeat expansion mutation of the Paired-like homeobox 2b (PHOX2B) gene, but the molecular mechanism of pathogenesis remains unknown. We found that introducing nonpolyalanine repeat expansion mutation of the PHOX2B into the mouse Phox2b locus recapitulates the clinical features of the CCHS associated with HSCR and NB. In mutant embryos, enteric and sympathetic ganglion progenitors showed sustained sex-determining region Y (SRY) box10 (Sox10) expression, with impaired proliferation and biased differentiation toward the glial lineage. Nonpolyalanine repeat expansion mutation of PHOX2B reduced transactivation of wild-type PHOX2B on its known target, dopamine β-hydroxylase (DBH), in a dominant-negative fashion. Moreover, the introduced mutation converted the transcriptional effect of PHOX2B on a Sox10 enhancer from repression to transactivation. Collectively, these data reveal that nonpolyalanine repeat expansion mutation of PHOX2B is both a dominant-negative and gain-of-function mutation. Our results also demonstrate that Sox10 regulation by PHOX2B is pivotal for the development and pathogenesis of the autonomic ganglia.
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hirschsprung disease associated syndromes and genetics a review
Journal of Medical Genetics, 2001Co-Authors: Jeanne Amiel, Stanislas LyonnetAbstract: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.
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molecular genetics of hirschsprung disease a model of multigenic Neurocristopathy
Biologie Aujourd'hui, 2000Co-Authors: Jeanne Amiel, Anna Pelet, Remi Salomon, Arnold Munnich, C Nihoulfekete, Renaud Touraine, Tania Attiebitach, Julie Steffann, Michel Vekemans, Stanislas LyonnetAbstract:Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic Neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB an EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.
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endothelin 3 gene mutations in isolated and syndromic hirschsprung disease
European Journal of Human Genetics, 1997Co-Authors: Christelle Bidaud, Tawab Attie, Anna Pelet, G. Van Camp, Patrick J. Willems, Maryse Bonduelle, Remi Salomon, Jeanne Amiel, C Nihoulfekete, Arnold MunnichAbstract:Abstract Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic Neurocristopathy. Four susceptibility genes have recently been identified in HSCR, namely the RET proto-oncogene, the glial cell line-derived neurotrophic factor (GDNF), the endothelin B receptor (EDNRB) and the endothelin-3 genes (EDN3). Homozygosity for EDN3 mutations has been previously shown to cause the Shah-Waardenburg syndrome, a combination of HSCR with features of the Waardenburg syndrome. Here, we report on heterozygous EDN3 missense mutations in isolatec HSCR. The present data give further support to the role of the endothelin signaling pathway in the development of neural crest-derived enteric neurons. They also suggest the possibility that either recessive or weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.
Tiziana Bachetti - One of the best experts on this subject based on the ideXlab platform.
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structural and functional differences in phox2b frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome
Human Mutation, 2018Co-Authors: Simona Di Lascio, Diego Fornasari, Roberta Benfante, Isabella Ceccherini, Silvia Cardani, Eleonora Di Zanni, Annalisa Adamo, Tiziana BachettiAbstract:Heterozygous mutations in the PHOX2B gene are causative of Congenital Central Hypoventilation Syndrome (CCHS), a Neurocristopathy characterised by defective autonomic control of breathing due to the impaired differentiation of neural crest cells (NCCs). Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This paper provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published. These were considered in terms of both their structure, whether the underlying indels induced frameshifts of either 1 or 2 steps (“frame 2″ and “frame 3″ mutations respectively), and clinical associations. Furthermore, we evaluated the structural and functional effects of one “frame 3″ mutation identified in a patient with isolated CCHS, and one “frame 2″ mutation identified in a patient with syndromic CCHS, also affected with Hirschsprung's disease and neuroblastoma. The data thus obtained confirm that the type of translational frame affects the severity of the transcriptional dysfunction and the predisposition to isolated or syndromic CCHS. This article is protected by copyright. All rights reserved
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1 Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in Congenital Central Hypoventilation Syndrome
2016Co-Authors: Tiziana Bachetti, Ivana Matera, Silvia Borghini, Marco Di Duca, Isabella CeccheriniAbstract:g.oxfordjournals.org/ D ow nloaded from 2 Congenital Central Hypoventilation Syndrome (CCHS) is a rare Neurocristopathy characterized by absence of adequate autonomic control of respiration with decreased sensitivity to hypoxia and hypercapnia. Frameshift mutations and polyalanine triplet expansions in the coding region of PHOX2B have been identified in the vast majority of CCHS patients and a correlation between length of the expanded region and severity of CCHS has been reported. In this work we have undertaken in vitro analyses aimed at identifying the pathogenetic mechanisms which underlie the effects of PHOX2B mutations in CCHS. According to the known role of this gene, a transcription factor expressed during autonomic nervou
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low amounts of phox2b expanded alleles in asymptomatic parents suggest unsuspected recurrence risk in congenital central hypoventilation syndrome
Journal of Molecular Medicine, 2011Co-Authors: Tiziana Bachetti, Marco Di Duca, Sara Parodi, Giuseppe Santamaria, Roberto Ravazzolo, Isabella CeccheriniAbstract:Heterozygous trinucleotide in frame duplications, leading to expansions of variable lengths of a 20-alanine stretch (polyAla), is the most frequent PHOX2B variant associated with congenital central hypoventilation syndrome (CCHS), a rare Neurocristopathy characterized by defective response of the autonomic nervous system to hypoxia and hypercapnia. Sequencing analysis has shown that the vast majority of polyAla expansions arise de novo; while in about 10% of cases, mutations are inherited by one parent who carries either constitutive or somatic mutations. To investigate transmission of PHOX2B mutant alleles from asymptomatic individuals, we have reassessed 44 parental pairs, previously resulted not to carry any mutation, by coupling amplification with FAM-tagged primers and capillary electrophoresis. Low levels of somatic mosaicism were shown in five parents previously undetected, thus increasing the inherited occurrence of the disease from 10% to 25% of the cases. Analysis of the technical detection limits has confirmed a power of resolution much higher for the "FAM" protocol than for the "sequencing" method. These observations are going to have relevant implications on how the carrier status of asymptomatic parents should be assessed and on successive genetic counseling to CCHS families.
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parental origin and somatic mosaicism of phox2b mutations in congenital central hypoventilation syndrome
Human Mutation, 2008Co-Authors: Syndrome Parodi, Tiziana Bachetti, Ivana Matera, Marco Di Duca, Giancarlo Ottonello, Francesca Lantieri, Giuseppe Santamaria, Roberto Ravazzolo, Isabella CeccheriniAbstract:Heterozygous polyalanine repeat expansions of PHOX2B have been associated with Congenital Central Hypoventilation Syndrome, a rare Neurocristopathy characterized by absence of adequate control of respiration during sleep. Here we report a PHOX2B mutational screening in 63 CCHS patients, 58 of whom presenting with poly-A expansions or frameshift, missense and nonsense mutations. To assess a somatic or germline occurrence of poly-A length variations, the relative amounts of mutant and wild type alleles have been quantified in 20 selected CCHS patients presenting with an expansion, and in their parents. Somatic mosaicism was shown in four parents, while no mosaic was found among CCHS patients. Moreover, while co-segregation analysis of the PHOX2B poly-A expansions with selected marker alleles in the same 20 CCHS trios has not demonstrated any parent-of-origin effect of the mutations, it has provided further clues to clarify the molecular mechanism underlying the expansion occurrence. Finally, the segregation of PHOX2B poly-A anomalous tracts within family members has allowed us to exclude tendency of polymorphic variations towards expansion. This strengthens the notion that expanded polyalanine tracts, identified as frequent disease-causing mutations also in other human diseases, are mitotically and meiotically stable.
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brainstem anomalies in two patients affected by congenital central hypoventilation syndrome
American Journal of Respiratory and Critical Care Medicine, 2006Co-Authors: Tiziana Bachetti, Isabella Ceccherini, Ivana Matera, Mp Baglietto, Angela Robbiano, Sara Parodi, Elisa Merello, Valeria Capra, Andrea Rossi, Giancarlo OttonelloAbstract:Congenital central hypoventilation syndrome (CCHS) is a rare Neurocristopathy characterized by absence of automatic control of respiration; decreased sensibility to hypoxia and hypercapnia, mainly during sleep; and autosomal dominant inheritance due to heterozygous polyalanine expansions and frameshift mutations in the PHOX2B gene. Because the CCHS phenotype could hide other neurologic diseases, the American Thoracic Society established that the initial evaluation of suspected CCHS should exclude neuroanatomic impairments as the structural basis of the reduced autonomic system function. In this work, we describe the clinical history of two unrelated patients with hypoventilation during sleep and harboring hypoplasia of the pons and a Chiari I malformation, respectively. In both patients, CCHS was diagnosed by detection of PHOX2B polyalanine expansion, suggesting that the American Thoracic Society diagnostic criteria may be too restrictive. Moreover, to exclude a putative role of PHOX2B in non-CCHS neurologic diseases, we have performed PHOX2B mutation screening in a group of individuals with Chiari I malformation, confirming the exclusive role of PHOX2B in the pathogenesis of CCHS.