ライフサイエンスコーパス: HSCR

1 HSCR is caused by the developmental failure of ENS proge

2 HSCR is characterized by the absence of ganglion cells i

3 HSCR is treated by surgical removal of aganglionic bowel

4 HSCR is typically managed by surgical removal of the aga

5 HSCR may be inherited as a single gene disorder with red

6 HSCR mutations have been identified in the RET receptor

7 We identify 22 HSCR-associated variants in candidate RET CREs, of which

8 ormed de novo mutation (DNM) screening on 24 HSCR trios.

9 uencing of SEMA3A, SEMA3C, and SEMA3D in 254 HSCR-affected subjects followed by in silico protein str

10 o haplotype sharing was evident in any of 36 HSCR kindreds typed for microsatellite markers surroundi

11 es of these variants in 997 samples from 376 HSCR families of European ancestry, that significant gen

12 present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GW

13 Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated

14 We identified one familial mutation in a HSCR patient with a known de novo RET mutation and malro

15 SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in RET CREs that af

16 variants in at least 10 RET enhancers affect HSCR risk, seven with experimental evidence of affecting

17 iptomic diversity of the ENS in controls and HSCR patients, as well as in wild-type and ret mutant ze

18 ne expression, and dysregulate other ENS and HSCR genes in the RET-EDNRB gene regulatory network (GRN

19 ived reinduction chemotherapy before HDT and HSCR.

20 Four patients received two cycles of HDT and HSCR.

21 these unique systems and in diseases such as HSCR and CAKUT.

22 ol(Tg/Tg), a model for trisomy 21-associated HSCR), TashT (TashT(Tg/Tg), a model for male-biased HSCR

23 /s-l), a model for EDNRB mutation-associated HSCR), and Ret(9/-) (with aganglionosis induced by mycop

24 ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis.

25 se chemotherapy (HDT) followed by autologous HSCR.

26 later in development and which might not be HSCR-associated.

27 TashT (TashT(Tg/Tg), a model for male-biased HSCR), Piebald-lethal (Ednrb(s-l//s-l), a model for EDNR

28 tor tyrosine kinase have been shown to cause HSCR.

29 leagues identify a new mechanism that causes HSCR-like disease in mice and involves deposition of exc

30 alence of continuous ventilatory dependence, HSCR, and neural crest tumors was seen in the nonpolyala

31 euroblastoma (NB) with Hirschsprung disease (HSCR) (aganglionosis of the terminal bowel) and congenit

32 netic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within cis-regulato

33 pathogenic alleles for Hirschsprung disease (HSCR) arise from coding and regulatory variants in genes

34 Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with

35 The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET.

36 Hirschsprung disease (HSCR) exhibits extensive genetic heterogeneity, with 72%

37 ionosis reminiscent of Hirschsprung disease (HSCR) in humans.

38 Hirschsprung disease (HSCR) is a common cause of intestinal obstruction in the

39 Hirschsprung disease (HSCR) is a common congenital disorder that results in in

40 The Hirschsprung disease (HSCR) is a complex congenital disorder, arising from abn

41 Hirschsprung disease (HSCR) is a complex disorder that exhibits incomplete pen

42 Hirschsprung disease (HSCR) is a congenital condition characterized by the imp

43 Hirschsprung disease (HSCR) is a human congenital disorder, defined by the abs

44 Hirschsprung disease (HSCR) is a life-threatening birth defect in which the di

45 Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in whi

46 Hirschsprung disease (HSCR) is a multigenic neurocristopathy clinically recogn

47 Hirschsprung disease (HSCR) is a multigenic, congenital disorder that affects

48 Hirschsprung disease (HSCR) is a neurocristopathy, yet paradoxically, neural c

49 Hirschsprung disease (HSCR) is a partially penetrant oligogenic birth defect t

50 Hirschsprung disease (HSCR) is a rare congenital intestinal disease that occur

51 The risk of Hirschsprung disease (HSCR) is approximately 15/100 000 live births per newbor

52 Hirschsprung disease (HSCR) is caused by a reduction of enteric neural crest c

53 Hirschsprung disease (HSCR) is characterized by absence of the enteric nervous

54 evidence suggests that Hirschsprung disease (HSCR) is the consequence of multiple gene interactions t

55 Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal ob

56 Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the

57 ) mice, an established Hirschsprung disease (HSCR) model, on distinct inbred backgrounds, C57BL/6J (B

58 Clinical expression of Hirschsprung disease (HSCR) requires the interaction of multiple susceptibilit

59 Hirschsprung disease (HSCR) results from defects in ENS formation; however, al

60 Hirschsprung disease (HSCR) results from incomplete NCC migration and failure

61 binding and increasing Hirschsprung disease (HSCR) risk 4-fold.

62 e treatment method for Hirschsprung disease (HSCR) since it is less invasive and has fewer morbiditie

63 dentified a regulatory Hirschsprung disease (HSCR) susceptibility variant.

64 e been associated with Hirschsprung disease (HSCR), a congenital disorder characterised by incomplete

65 is segmentally lost in Hirschsprung disease (HSCR), a consequence of cell-autonomous and non-autonomo

66 Hirschsprung disease (HSCR), a multifactorial disorder of enteric nervous syst

67 on RET mutations cause Hirschsprung disease (HSCR), in which infants are born with aganglionic bowel.

68 l embryos, a model for Hirschsprung disease (HSCR), in which the ENS is absent.

69 lon, commonly known as Hirschsprung disease (HSCR), is the most frequent cause of congenital bowel ob

70 Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most

71 Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most

72 Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a rela

73 Hirschsprung disease (HSCR), the most common hereditary cause of intestinal ob

74 Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, res

75 oF) is associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastroint

76 ionosis reminiscent of Hirschsprung disease (HSCR).

77 man congenital disease Hirschsprung disease (HSCR).

78 an disorders including Hirschsprung disease (HSCR).

79 a hallmark feature of Hirschsprung disease (HSCR).

80 Hirschsprung disease (HSCR, MIM #142623) is a multigenic neurocristopathy (neu

81 Hirschsprung's disease (HSCR) causes functional intestinal obstruction due to th

82 Hirschsprung's disease (HSCR) is a severe congenital anomaly of the enteric nerv

83 the colon results in Hirschsprung's disease (HSCR) or colonic aganglionosis.

84 europathies, such as Hirschsprung's disease (HSCR), achalasia, intestinal neuronal dysplasia (IND), c

85 al disorders such as Hirschsprung's disease (HSCR), in which the ENS plays a pivotal role.

86 n in humans known as Hirschsprung's disease (HSCR).

87 pment is relevant to Hirschsprung's disease (HSCR; congenital aganglionosis of the terminal bowel), w

88 The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic mo

89 For almost every HSCR gene, incomplete penetrance of the HSCR phenotype h

90 in group I families is sufficient to explain HSCR inheritance, a genome scan reveals a new susceptibi

91 els to comprehensively capture epistasis for HSCR between and within RET and NRG1 loci using whole ge

92 ying these mutations should be evaluated for HSCR and neural crest tumors.

93 clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM compos

94 e report the generation of a mouse model for HSCR--named Holstein--that contains an untargeted transg

95 re normal has guided surgical procedures for HSCR patients.

96 ve effects of regulatory variants in RET for HSCR.

97 mice (Plp1-GFP;Baf-tdT;Ednrb(-/-)) and human HSCR tissues.

98 t to establish a possible link between human HSCR and mutations affecting the Gdnf locus, we studied

99 to the variable aganglionosis seen in human HSCR families.

100 (LAMR), which binds laminin-beta1, in human HSCR myenteric plexus and EdnrB(NCC-/-) NCC.

101 onic segment, and sex bias observed in human HSCR patients.

102 ptor B (EdnrB) mutation reliably model human HSCR and HAEC.

103 olon hypoganglionosis, which resembles human HSCR.

104 st that GDNF is a minor contributor to human HSCR susceptibility and that loss of its function in ent

105 In HSCR, ganglionic segments mirrored controls and aganglio

106 One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B

107 we review studies evaluating ENS defects in HSCR and non-HSCR mouse models, concluding with clinical

108 No evidence of linkage was detected in HSCR kindreds and no mutations were found in patients.

109 No evidence of linkage was detected in HSCR kindreds, and no sequence variants were found to be

110 or could be involved in sexual dimorphism in HSCR.

111 thereby contributing to sexual dimorphism in HSCR.

112 e effects could contribute to dysmotility in HSCR, which predominantly affects males, and uncovers a

113 t 12 different genes have been identified in HSCR patients but the complex pattern of inheritance and

114 ption factor, SOX10, have been identified in HSCR patients.

115 our attention on the enhancer implicated in HSCR to demonstrate that this element drives reporter ex

116 elin receptor type B (EDNRB) are involved in HSCR pathogenesis; however, also important in ENS develo

117 ecursors rescue disease-related mortality in HSCR mice (Ednrb(s-l/s-l)), although the mechanism of ac

118 Cs failed to reach the hindgut, resulting in HSCR-like phenotypes.

119 system consistent with its proposed role in HSCR.

120 embryos, it does not play an obvious role in HSCR.

121 Studies in HSCR families have identified RET-dependent modifiers fo

122 patients after surgery as well as studies in HSCR mouse models suggest that aberrant NC segregation a

123 of impaired stromal-epithelial cross-talk in HSCR and the pathogenesis of HAEC and suggest potential

124 f HSCR and suggest a mechanism for increased HSCR incidence in children with Down syndrome (trisomy 2

125 than complete loss, is sufficient to induce HSCR, ii) Ret and Ednrb demonstrate strong trans interac

126 r data open new fields of investigation into HSCR pathology and provide novel insights into the devel

127 Isolated HSCR has an oligogenic inheritance with RET as the major

128 genes are involved in familial and isolated HSCR, of which the most common are the RET proto-oncogen

129 To determine whether known HSCR susceptibility loci are acting as modifiers of Sox1

130 R), but epistatic effects in long-segment (L-HSCR) and syndromic cases have not been fully explained.

131 DNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmi

132 he DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not

133 wild-type and EdnrB(NCC-/-) mice that model HSCR and identified laminin-beta1 as upregulated in Ednr

134 enotypic expression by studying 12 multiplex HSCR families.

135 , which is downregulated in human and murine HSCR.

136 entilation syndrome (CCHS) (also known as NB-HSCR-CCHS), linked to mutations in PHOX2B.

137 udies evaluating ENS defects in HSCR and non-HSCR mouse models, concluding with clinical implications

138 throughout the length of the intestine (non-HSCR) have also found that certain genetic alterations a

139 We identify and validate novel HSCR genes using whole exome sequencing (WES), burden te

140 However, 80% of HSCR patients have short-segment Hirschsprung disease (S

141 mental in the identification and analysis of HSCR disease genes.

142 er insights into the genetic architecture of HSCR and has profound implications for future study desi

143 S development and suggest that some cases of HSCR may be preventable.

144 r, GDNF has been implicated in rare cases of HSCR.

145 ificant and life-threatening complication of HSCR, affecting up to 60% of patients.

146 congenital origin, the molecular etiology of HSCR remains elusive for >70% of patients.

147 in mice models many of the early features of HSCR.

148 try individuals, is involved in all forms of HSCR.

149 and up to one-third of the sporadic forms of HSCR.

150 supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in

151 type B (EDNRB) are central to the genesis of HSCR.

152 ome of the so-called missing heritability of HSCR and suggest a mechanism for increased HSCR incidenc

153 The inheritance of HSCR is complex, often non-Mendelian and characterized b

154 Another mouse model of HSCR disease, Dom, arose spontaneously at the Jackson La

155 ll mutant ENS precursors enable modelling of HSCR-related migration defects, and the identification o

156 In 2 different mouse models of HSCR, addition of mycophenolate increased the penetrance

157 rvous system regeneration in mouse models of HSCR.

158 structure and function in 3 mouse models of HSCR.

159 performed studies with four mouse models of HSCR: Holstein (Hol(Tg/Tg), a model for trisomy 21-assoc

160 As such, the gene at 9q31 is a modifier of HSCR penetrance.

161 Loss-of-function mutations of HSCR genes and haploinsufficiency of their gene products

162 The functional outcomes of HSCR patients after TEPT in our institution are consider

163 d the gene for mutations in a large panel of HSCR patients.

164 nned for GFRA1 mutations in a large panel of HSCR patients.

165 ith a predisposition for the pathogenesis of HSCR.

166 ys to accurately assess the pathogenicity of HSCR-associated variants rather than relying solely on b

167 atures of the complex inheritance pattern of HSCR.

168 lopmental program; 3) expression patterns of HSCR-associated and Ret gene regulatory network genes ar

169 protein haploinsufficiency and promotion of HSCR development, thereby contributing to sexual dimorph

170 risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7.

171 together, make contributions to the risk of HSCR.

172 candidate genes for human genetic studies of HSCR.

173 pigmentary anomalies typical of a subset of HSCR patients categorized as Waardenburg-Shah syndrome (

174 Subsets of HSCR individuals also present with neural crest-derived

175 d drug-based strategies for the treatment of HSCR.

176 GDNF might be developed for treatment of HSCR.

177 that persist after the surgical treatment of HSCR.

178 ols, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putative

179 actors (TFs) RARB, GATA2 and SOX10 and other HSCR genes.

180 ontinued gastric dysmotility in postsurgical HSCR patients.

181 s have short-segment Hirschsprung disease (S-HSCR), which has not been associated with genetic factor

182 f the much more common short-segment form (S-HSCR).

183 ependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-HSCR) an

184 dissection why the inheritance pattern of S-HSCR is nonmendelian.

185 Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers

186 mutation in RET) and from 2 patients with S-HSCR (without a RET mutation), as well as RET(+/-) and R

187 e conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 a

188 e searched for mutation(s) associated with S-HSCR by combining genetic and transcriptome data from pa

189 ught to identify mutations associated with S-HSCR, and used the clustered regularly interspaced short

190 dentified mutations in VCL associated with S-HSCR.

191 tion in the vinculin gene (VCL M209L) with S-HSCR.

192 ed RET-dependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-

193 Here, functional outcomes in short-segment HSCR patients after TEPT were assessed and associated wi

194 In addition, a splice isoform-specific HSCR missense mutation, which does not inactivate the RE

195 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much mo

196 SOX10 mutations contribute to syndromic HSCR cases and Sox10 alleles in mice exhibit aganglionos

197 , disrupted expression of both Sox10 and the HSCR disease gene Ednrb in Dom mutant embryos, and loss

198 Stromal cells from the HSCR distal ganglionic colon failed to sustain the growt

199 Recent studies identified over half of the HSCR disease susceptibility genes as targets for the sex

200 very HSCR gene, incomplete penetrance of the HSCR phenotype has been observed, probably due to geneti

201 induced neurogenesis partially rescuing the HSCR phenotype in ret(+/-) mutants.

202 Thus, HSCR has become a model of a complex polygenic disorder

203 grative, regenerative medicine approaches to HSCR.

204 tion, and defects in these processes lead to HSCR.

205 c and nongenetic factors have been linked to HSCR, the underlying mechanisms that prevent ENS precurs

206 isposition of patients with Down syndrome to HSCR.

207 Genetic defects underlie HSCR, but much of the variability in the occurrence and

208 g variants in 13 genes are known to underlie HSCR risk, with the most frequent variants in the ret pr

209 dies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not

210 Knowledge of the genetics underlying HSCR is incomplete, particularly genes that control cell

211 pic classes with defined risks to understand HSCR etiology.

212 We screened 106 unrelated HSCR patients for mutations in GDNF by direct sequencing

213 cyte deficiencies (Hirschsprung-Waardenburg, HSCR-WS, MIM #277580).

214 Syndromes associated with HSCR include trisomy 21, Mowat-Wilson syndrome, congenit

215 One of the genes associated with HSCR is endothelin receptor type B (Ednrb).

216 in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribu

217 related transcription factor associated with HSCR, in the Ednrb ENS enhancer, and mutational analyses

218 ants of aganglionic bowel from children with HSCR induced proliferation of Schwann cells and formatio

219 ganglionic colon explants from children with HSCR were cultured with GDNF and evaluated for neurogene

220 Our results suggest that HDT with HSCR is an effective treatment for patients with Wilms'

221 In individuals with HSCR but without epithelial damage, the distal ganglioni

222 candidate disease gene for individuals with HSCR whose disease does not have an identified genetic o

223 ess the functional outcomes in patients with HSCR after TEPT surgery at our institution from 2012 to

224 Using colonic tissue from patients with HSCR alongside the well-established endothelin receptor

225 Patients with HSCR also exhibited remodeling in stromal cells in this

226 Despite surgical correction, patients with HSCR often experience chronic defecatory dysfunction and

227 al from pediatric controls and patients with HSCR was collected, dissociated, and enriched for the EN

228 ene are frequently detected in patients with HSCR, mutations in the gene encoding its ligand (glial c

229 ist in aganglionic segments of patients with HSCR, offering a new target for their treatment using 5-