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E. Michelle Southard-smith - One of the best experts on this subject based on the ideXlab platform.
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Genome-wide linkage identifies novel modifier loci of Aganglionosis in the Sox10Dom model of Hirschsprung disease
Human molecular genetics, 2005Co-Authors: Sarah E. Owens, Karl W. Broman, Tim Wiltshire, J. Bradford Elmore, Kevin M. Bradley, Jeffrey R. Smith, E. Michelle Southard-smithAbstract:Hirschsprung disease (HSCR) is a complex disorder that exhibits incomplete penetrance and variable expressivity due to interactions among multiple susceptibility genes. Studies in HSCR families have identified RET-dependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-HSCR) and syndromic cases have not been fully explained. SOX10 mutations contribute to syndromic HSCR cases and Sox10 alleles in mice exhibit Aganglionosis and pigmentary anomalies typical of a subset of HSCR patients categorized as Waardenburg-Shah syndrome (WS4, OMIM 277580). Sox10 mutant alleles in mice exhibit strain-dependent variation in penetrance and expressivity of aganglionic megacolon analogous to the variation observed in patients with Aganglionosis. In this study, we focused on enteric ganglia deficits in Sox10Dom mice and defined Aganglionosis as a quantitative trait in Sox10Dom intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. We observe that the phenotype of Sox10Dom/+ mutants ranges over a continuum from severe Aganglionosis to no detectable phenotype in the gut. To systematically identify genes that modulate Sox10-dependent Aganglionosis, we performed a single nucleotide polymorphism-based genome scan in Sox10Dom/+ F1 intercross progeny. Our analysis reveals modifier loci on mouse chromosomes 3, 5, 8, 11 and 14 with distinct effects on penetrance and severity of Aganglionosis. Three of these loci on chromosomes 3, 8 and 11 do not coincide with previously known Aganglionosis susceptibility genes or modifier loci and offer new avenues for elucidating the genetic network that modulates this complex neurocristopathy.
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Interactions between Sox10 and EdnrB modulate penetrance and severity of Aganglionosis in the Sox10Dom mouse model of Hirschsprung disease.
Human molecular genetics, 2004Co-Authors: V. Ashley Cantrell, Sarah E. Owens, Kevin M. Bradley, Jeffrey R. Smith, Ronald L. Chandler, C D C David Airey, E. Michelle Southard-smithAbstract:Cumulative evidence suggests that Hirschsprung disease (HSCR) is the consequence of multiple gene interactions that modulate the ability of enteric neural crest (NC) cells to populate the developing gut. One of the essential genes for this process is the NC transcription factor Sox10. Sox10 Dom mice on a mixed genetic background show variation in penetrance and expressivity of enteric Aganglionosis that are analogous to the variable Aganglionosis seen in human HSCR families. The phenotype of Sox10 Dom mice in congenic lines indicates this variation arises from modifiers in the genetic background. To determine whether known HSCR susceptibility loci are acting as modifiers of SoxlO, we tested for association between genes in the endothelin signaling pathway (EdnrB, Edn3, Ece1) and severity of Aganglionosis in an extended pedigree of B6C3FeLe.Sox10 Dom mice. Single locus association analysis in this pedigree identifies interaction between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a highly significant effect of EdnrB alleles on the Sox10 Dom/+ phenotype. The presence of C57BL/6J alleles at EdnrB is associated with increased penetrance and more severe Aganglionosis in Sox10 Dom mutants. Crosses between EdnrB and SoxlO mutants corroborate this gene interaction with double mutant progeny exhibiting significantly more severe Aganglionosis. The background strain of the EdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant progeny implying the action of additional modifiers on this phenotype. Our data demonstrates that Sox10-EdnrB interactions can influence development of the enteric nervous system in mouse models and suggests that this interaction could contribute to the epistatic network producing variation between patients with Aganglionosis.
James C.y. Dunn - One of the best experts on this subject based on the ideXlab platform.
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Delayed appearance of mature ganglia in an infant with an atypical presentation of total colonic and small bowel Aganglionosis: a case report
BMC, 2019Co-Authors: Fereshteh Salimi Jazi, James C.y. Dunn, Julia M. Chandler, Chad M. Thorson, Tiffany J. Sinclair, Florette K. Hazard, John A. Kerner, Sanjeev Dutta, Stephanie D. ChaoAbstract:Abstract Background Total colonic and small bowel Aganglionosis (TCSA) occurs in less than 1% of all Hirschsprung’s disease patients. Currently, the mainstay of treatment is surgery. However, in patients with TCSA, functional outcomes are often poor. A characteristic transition zone in TCSA can be difficult to identify which may complicate surgery and may often require multiple operations. Case presentation We present the case of a male infant who was diagnosed with biopsy-proven total colonic Aganglionosis with extensive small bowel involvement as a neonate. The patient was diverted at one month of age based on leveling biopsies at 10 cm from the Ligament of Treitz. At 7 months of age, during stoma revision for a prolapsed stoma, intra-operative peristalsis was observed in nearly the entire length of the previously aganglionic bowel, and subsequent biopsies demonstrated the appearance of mature ganglion cells in a previously aganglionic segment. Conclusions TCSA remains a major challenge for pediatric surgeons. Our case introduces new controversy to our understanding of Aganglionosis. Our observations warrant further research into the possibility of post-natal ganglion maturation and encourage surgeons to consider a more conservative surgical approach
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a novel in vivo model of permanent intestinal Aganglionosis
Journal of Surgical Research, 2014Co-Authors: Justin P. Wagner, Veronica F. Sullins, James C.y. DunnAbstract:Abstract Background Enteric neuromuscular disease is a characteristic of several disease states, including Hirschsprung disease, esophageal achalasia, Chagas disease, and gastroparesis. Medical therapy for these conditions is limited, and surgical intervention may incur significant morbidity. Alternatively, transplantation of neural progenitor cells may regenerate enteric ganglia. Existing Aganglionosis model systems are limited by swift animal demise or by spontaneous regeneration of native ganglia. We propose a novel protocol to induce permanent Aganglionosis in a segment of rat jejunum, which may serve as an experimental transplantation target for cellular therapy. Materials and methods This protocol was performed in 17 adult female Sprague–Dawley rats. A laparotomy was performed and a 1-cm segment of jejunum was isolated from continuity. Among 14 rats, the isolated segments were treated with benzalkonium chloride (BAC) for 20 min to induce Aganglionosis. Jejunal segment isolation was performed without BAC treatment in three rats. The animals were euthanized at posttreatment days 21–166. Muscle layer diameter was compared among normal, isolated, and BAC-treated isolated jejunal segments. The presence of jejunal ganglia was documented by immunohistochemical staining (IHC) for beta-III tubulin (TUJ1) and S100, markers of neuronal and glial cell lineages, respectively. Results Ganglia were identified by IHC in normal and isolated jejunal segments. Isolated segments had significantly hypertrophied smooth muscle layers compared with normal jejunum (diameter 343 ± 53 μm versus 211 ± 37 μm, P Conclusions The exclusion of a jejunal segment from continuity and concurrent treatment with BAC results in an effective, reproducible, and permanent model of Aganglionosis. Muscular hypertrophy and Aganglionosis in the isolated jejunal segment make it an ideal recipient site for transplantation of neuroglial precursor cells.
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A novel in vivo model of permanent intestinal Aganglionosis.
The Journal of surgical research, 2014Co-Authors: Justin P. Wagner, Veronica F. Sullins, James C.y. DunnAbstract:Enteric neuromuscular disease is a characteristic of several disease states, including Hirschsprung disease, esophageal achalasia, Chagas disease, and gastroparesis. Medical therapy for these conditions is limited, and surgical intervention may incur significant morbidity. Alternatively, transplantation of neural progenitor cells may regenerate enteric ganglia. Existing Aganglionosis model systems are limited by swift animal demise or by spontaneous regeneration of native ganglia. We propose a novel protocol to induce permanent Aganglionosis in a segment of rat jejunum, which may serve as an experimental transplantation target for cellular therapy. This protocol was performed in 17 adult female Sprague-Dawley rats. A laparotomy was performed and a 1-cm segment of jejunum was isolated from continuity. Among 14 rats, the isolated segments were treated with benzalkonium chloride (BAC) for 20 min to induce Aganglionosis. Jejunal segment isolation was performed without BAC treatment in three rats. The animals were euthanized at posttreatment days 21-166. Muscle layer diameter was compared among normal, isolated, and BAC-treated isolated jejunal segments. The presence of jejunal ganglia was documented by immunohistochemical staining (IHC) for beta-III tubulin (TUJ1) and S100, markers of neuronal and glial cell lineages, respectively. Ganglia were identified by IHC in normal and isolated jejunal segments. Isolated segments had significantly hypertrophied smooth muscle layers compared with normal jejunum (diameter 343 ± 53 μm versus 211 ± 37 μm, P < 0.0001). BAC-treated jejunal segments had no IHC evidence of ganglionic structures. Aganglionosis was persistent in all specimens up to 166 days after treatment. The exclusion of a jejunal segment from continuity and concurrent treatment with BAC results in an effective, reproducible, and permanent model of Aganglionosis. Muscular hypertrophy and Aganglionosis in the isolated jejunal segment make it an ideal recipient site for transplantation of neuroglial precursor cells. Copyright © 2014 Elsevier Inc. All rights reserved.
Sarah E. Owens - One of the best experts on this subject based on the ideXlab platform.
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Genome-wide linkage identifies novel modifier loci of Aganglionosis in the Sox10Dom model of Hirschsprung disease
Human molecular genetics, 2005Co-Authors: Sarah E. Owens, Karl W. Broman, Tim Wiltshire, J. Bradford Elmore, Kevin M. Bradley, Jeffrey R. Smith, E. Michelle Southard-smithAbstract:Hirschsprung disease (HSCR) is a complex disorder that exhibits incomplete penetrance and variable expressivity due to interactions among multiple susceptibility genes. Studies in HSCR families have identified RET-dependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-HSCR) and syndromic cases have not been fully explained. SOX10 mutations contribute to syndromic HSCR cases and Sox10 alleles in mice exhibit Aganglionosis and pigmentary anomalies typical of a subset of HSCR patients categorized as Waardenburg-Shah syndrome (WS4, OMIM 277580). Sox10 mutant alleles in mice exhibit strain-dependent variation in penetrance and expressivity of aganglionic megacolon analogous to the variation observed in patients with Aganglionosis. In this study, we focused on enteric ganglia deficits in Sox10Dom mice and defined Aganglionosis as a quantitative trait in Sox10Dom intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. We observe that the phenotype of Sox10Dom/+ mutants ranges over a continuum from severe Aganglionosis to no detectable phenotype in the gut. To systematically identify genes that modulate Sox10-dependent Aganglionosis, we performed a single nucleotide polymorphism-based genome scan in Sox10Dom/+ F1 intercross progeny. Our analysis reveals modifier loci on mouse chromosomes 3, 5, 8, 11 and 14 with distinct effects on penetrance and severity of Aganglionosis. Three of these loci on chromosomes 3, 8 and 11 do not coincide with previously known Aganglionosis susceptibility genes or modifier loci and offer new avenues for elucidating the genetic network that modulates this complex neurocristopathy.
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Interactions between Sox10 and EdnrB modulate penetrance and severity of Aganglionosis in the Sox10Dom mouse model of Hirschsprung disease.
Human molecular genetics, 2004Co-Authors: V. Ashley Cantrell, Sarah E. Owens, Kevin M. Bradley, Jeffrey R. Smith, Ronald L. Chandler, C D C David Airey, E. Michelle Southard-smithAbstract:Cumulative evidence suggests that Hirschsprung disease (HSCR) is the consequence of multiple gene interactions that modulate the ability of enteric neural crest (NC) cells to populate the developing gut. One of the essential genes for this process is the NC transcription factor Sox10. Sox10 Dom mice on a mixed genetic background show variation in penetrance and expressivity of enteric Aganglionosis that are analogous to the variable Aganglionosis seen in human HSCR families. The phenotype of Sox10 Dom mice in congenic lines indicates this variation arises from modifiers in the genetic background. To determine whether known HSCR susceptibility loci are acting as modifiers of SoxlO, we tested for association between genes in the endothelin signaling pathway (EdnrB, Edn3, Ece1) and severity of Aganglionosis in an extended pedigree of B6C3FeLe.Sox10 Dom mice. Single locus association analysis in this pedigree identifies interaction between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a highly significant effect of EdnrB alleles on the Sox10 Dom/+ phenotype. The presence of C57BL/6J alleles at EdnrB is associated with increased penetrance and more severe Aganglionosis in Sox10 Dom mutants. Crosses between EdnrB and SoxlO mutants corroborate this gene interaction with double mutant progeny exhibiting significantly more severe Aganglionosis. The background strain of the EdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant progeny implying the action of additional modifiers on this phenotype. Our data demonstrates that Sox10-EdnrB interactions can influence development of the enteric nervous system in mouse models and suggests that this interaction could contribute to the epistatic network producing variation between patients with Aganglionosis.
Seung Eun Jung - One of the best experts on this subject based on the ideXlab platform.
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outcomes of surgical management of total colonic Aganglionosis
World Journal of Surgery, 2008Co-Authors: Eunkyung Choe, Suk-bae Moon, Hyoki Kim, Sang Chul Lee, Kyungwoo Park, Seung Eun JungAbstract:Purpose The purpose of this study was to assess the long-term clinical outcomes and bowel function of patients with total colonic Aganglionosis (TCA) after surgery.
S. W. Moore - One of the best experts on this subject based on the ideXlab platform.
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Total colonic Aganglionosis and Hirschsprung’s disease: a review
Pediatric Surgery International, 2015Co-Authors: S. W. MooreAbstract:Total colonic Aganglionosis is a relatively uncommon form of Hirschsprung’s disease (HSCR). It occurs in approximately 2–13 % of HSCR cases and involves the entire colon which is aganglionic but may extend proximally into varying lengths of small bowel. As a result, it should be separated into Total colonic Aganglionosis (TCA) [defined as Aganglionosis extending from the anus to at least the ileocaecal valve but no more than 50 cm small bowel proximal to the ileocaecal valve] and total colonic and small bowel Aganglionosis (TCSA) which may involve very long segments of small bowel Aganglionosis. Clinically, TCA appears to represent a different spectrum of disease in terms of presentation and difficulties which may be experienced in diagnosis suggesting a different pathophysiology from the more common forms of HSCR. It is therefore not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. A number of differences exist between TCA and other forms of HSCR which require explanation if its ubiquitous clinical features are to be understood. In addition to the usual explanations for the Aganglionosis of HSCR, there is some evidence suggesting that in place of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews what is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment; S-HSCR) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.
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total colonic Aganglionosis and hirschsprung s disease a review
Pediatric Surgery International, 2015Co-Authors: S. W. MooreAbstract:Total colonic Aganglionosis is a relatively uncommon form of Hirschsprung’s disease (HSCR). It occurs in approximately 2–13 % of HSCR cases and involves the entire colon which is aganglionic but may extend proximally into varying lengths of small bowel. As a result, it should be separated into Total colonic Aganglionosis (TCA) [defined as Aganglionosis extending from the anus to at least the ileocaecal valve but no more than 50 cm small bowel proximal to the ileocaecal valve] and total colonic and small bowel Aganglionosis (TCSA) which may involve very long segments of small bowel Aganglionosis. Clinically, TCA appears to represent a different spectrum of disease in terms of presentation and difficulties which may be experienced in diagnosis suggesting a different pathophysiology from the more common forms of HSCR. It is therefore not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. A number of differences exist between TCA and other forms of HSCR which require explanation if its ubiquitous clinical features are to be understood. In addition to the usual explanations for the Aganglionosis of HSCR, there is some evidence suggesting that in place of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews what is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment; S-HSCR) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.
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Total colonic Aganglionosis in Hirschsprung disease.
Seminars in pediatric surgery, 2012Co-Authors: S. W. MooreAbstract:Total colonic Aganglionosis (TCA) is a relatively uncommon form of Hirschsprung disease (HSCR), occurring in approximately 2%-13% of cases. It can probably be classified as TCA (defined as Aganglionosis extending from the anus to at least the ileocecal valve, but not >50 cm proximal to the ileocecal valve) and total colonic and small bowel Aganglionosis, which may involve a very long segment of Aganglionosis. It is not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. There are many differences between TCA and other forms of HSCR, which require explanation if its ubiquitous clinical features are to be understood. Clinically, TCA appears to represent a different spectrum of disease in terms of presentation and difficulties that may be experienced in diagnosis, suggesting a different pathophysiology from the more common forms of HSCR. There is also some evidence suggesting that instead of being purely congenital, it may represent certain different pathophysiologic mechanisms. This study, in addition to reviewing current understanding and differences between TCA and the more frequently encountered rectosigmoid (or short-segment) expression, correlates them with what is currently known about the genetic and molecular biological background. Moreover, it reviews current outcomes to find consensus on management.
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Total colonic Aganglionosis and Hirschsprung’s disease: shades of the same or different?
Pediatric Surgery International, 2009Co-Authors: S. W. MooreAbstract:Total colonic Aganglionosis is a relatively uncommon form of Hirschsprung’s disease (HSCR) occurring in approximately 2–13% of cases. It can probably be divided into total colonic Aganglionosis (TCA; defined as Aganglionosis extending from the anus to at least the ileocaecal valve, but no more than 50 cm proximal to the ileocaecal valve) and total colonic and small bowel Aganglionosis, which may involve a very long segment of Aganglionosis. Clinically, they appear to represent a different spectrum of disease in terms of presentation and difficulties in diagnosis which may be experienced, suggesting a different pathophysiology from the more common forms of HSCR. It is not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. There are a number of differences between TCA and other forms of HSCR, which require an explanation if its ubiquitous clinical features are to be understood. There is some evidence suggesting that instead of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews all that is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.
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total colonic Aganglionosis and hirschsprung s disease shades of the same or different
Pediatric Surgery International, 2009Co-Authors: S. W. MooreAbstract:Total colonic Aganglionosis is a relatively uncommon form of Hirschsprung’s disease (HSCR) occurring in approximately 2–13% of cases. It can probably be divided into total colonic Aganglionosis (TCA; defined as Aganglionosis extending from the anus to at least the ileocaecal valve, but no more than 50 cm proximal to the ileocaecal valve) and total colonic and small bowel Aganglionosis, which may involve a very long segment of Aganglionosis. Clinically, they appear to represent a different spectrum of disease in terms of presentation and difficulties in diagnosis which may be experienced, suggesting a different pathophysiology from the more common forms of HSCR. It is not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. There are a number of differences between TCA and other forms of HSCR, which require an explanation if its ubiquitous clinical features are to be understood. There is some evidence suggesting that instead of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews all that is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.
