Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease

Gunadi, Gunadi; Kapoor, Ashish; Ling, Albee Y.; Rochadi, .; Makhmudi, Akhmad; Herini, Elisabeth Siti; Sosa, Maria X.; Chatterjee, Satadal; Chakravarti, Aravinda

doi:10.1016/j.jpedsurg.2014.04.011

Cited by 36 publications

(42 citation statements)

References 18 publications

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“…Mutation and functional changes of these genes had been indicated, whereas the details of the regulations are still not well known. In recent years, some novel genes have been detected in the segments of HD, such as WNT3A [17], MeCP2 [18], NRG1 [19], etc, but none of these were found to further promote the pathogenesis. Our results showed that autophagy, an evolutionarily process, was involved in HD.…”

Section: Discussionmentioning

confidence: 99%

Detection of autophagy in Hirschsprung’s disease

Huang¹,

Ge²,

Li³

et al. 2015

NeuroReport

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Hirschsprung's disease (HD) is a common congenital gastrointestinal malformation, characterized by the lack of ganglion cells from the distal rectum to the proximal bowel, but the pathogenesis is not well understood. This paper evaluates the effects of autophagy in HD. Using electron microscopy, the autophagosomes were detected in three segments: narrow segment (NS), transitional segment (TS), and dilated segment (DS). Typical autophagosome structures are found in the Auerbach plexus of both NS and TS. Real-time PCR results showed that Beclin1 (NS vs. TS, P<0.01) and LC3 (NS vs. TS, P<0.05) mRNA were the highest in the NS, but p75 (NS vs. TS, P<0.01) was the highest in the DS. Correlation analysis results showed a positive correlation between Beclin1 and LC3 mRNA levels (R=0.736, P=0.000), whereas inverse correlations were found between p75 and Beclin1/LC3 mRNA levels (p75 vs. Beclin1: R=-0.714, P=0.000; p75 vs. LC3: R=-0.619, P=0.000). Immunohistochemistry analyses indicated a consistent result with mRNA levels, by increased Beclin1-positive and LC3-positive neurons, but reduced p75-positive neurons in the Auerbach plexus of TS compared with DS. These findings indicated that autophagy exists in the bowel of patients with HD. On the basis of the detection of the highest expression of the autophagy genes in NS, autophagy may additionally cause the lack of neurons.

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Section: Discussionmentioning

confidence: 99%

Detection of autophagy in Hirschsprung’s disease

Huang¹,

Ge²,

Li³

et al. 2015

NeuroReport

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“…13 Other examples are NRG1 common variants rs16879552 and rs7835688. These polymorphisms have been related to Hirschsprung disease in Asian ancestry cases [14][15][16] ; however, they are not associated with Hirschsprung disease in white ancestry patients. 17,18 a The gene and variants genotyped, allele frequencies in infants with gastroschisis and controls, the OR, and its 95% CI, with statistical significance values (P values), are shown.…”

Section: Discussionmentioning

confidence: 89%

ICAM1K469E Polymorphism Effect in Gastroschisis Patients

et al. 2018

Self Cite

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Objective: To evaluate the association between a common cell-cell interaction variant, intracellular adhesion molecule 1 (ICAM1) K469E, and gastroschisis risk in Indonesia. Summary of Background Data: Gastroschisis is a congenital disorder characterized by fetal intestines' extrusion outside the body. Several hypotheses have been proposed for gastroschisis, including an impairment in the normal attachment between umbilical cord and umbilical ring. Methods: A total of 48 infants with gastroschisis and 88 ethnicity-matched controls were involved in this study. The ICAM1 K469E polymorphism was analyzed using polymerase chain reaction-restriction fragment-length polymorphisms on genomic DNA. Results: The frequencies of genotypes for ICAM1 K469E in patients were KK, 30 of 48 (63%); KE, 17 of 48 (35%); and EE, 1 of 48 (2%), whereas their frequencies in controls were KK, 48 of 88 (55%); KE, 33 of 88 (37%); and EE, 7 of 88 (8%). Those frequencies were not significantly different between both groups (P ¼ 0.37) with an OR of 1.39 (95% CI, 0.68-2.85). The K469 allele had a frequency of 80% (77 of 96) in patients and 73% (129 of 176) in controls, and the frequency in patients was not significantly higher than that in controls (P ¼ 0.20), with an odds ratio of 1.48 (95% confidence interval, 0.81-2.70). In addition, the frequency of ICAM1 K469 allele in patients with maternal age younger than 25 years was

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“…This is important because known genetic causes for HSCR are partially penetrant suggesting gene-gene or gene-environment interactions cause HSCR. This was demonstrated dramatically in mice by the observation that Ret+/− mice never have distal bowel aganglionosis (McCallion et al, 2003), but develop HSCR-like disease more readily than WT when other mutations or non-genetic risk factors are present (Arnold et al, 2009; Carrasquillo et al, 2002; Fu et al, 2010; Gunadi et al, 2014; Lake et al, 2013; McCallion et al, 2003; Phusantisampan et al, 2012; Wallace and Anderson, 2011). In contrast to mice, humans with a single inactive RET allele (i.e., ~30% of HSCR cases) have about a 50% chance of having HSCR (Amiel et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse

Schill

Lake

Tusheva

et al. 2016

Developmental Biology

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Hirschsprung Disease (HSCR) is a potentially deadly birth defect characterized by the absence of the enteric nervous system (ENS) in distal bowel. Although HSCR has clear genetic causes, no HSCR-associated mutation is 100% penetrant, suggesting gene-gene and gene-environment interactions determine HSCR occurrence. To test the hypothesis that certain medicines might alter HSCR risk we treated zebrafish with medications commonly used during early human pregnancy and discovered that ibuprofen caused HSCR-like absence of enteric neurons in distal bowel. Using fetal CF-1 mouse gut slice cultures, we found that ibuprofen treated enteric neural crest-derived cells (ENCDC) had reduced migration, fewer lamellipodia and lower levels of active RAC1/CDC42. Additionally, inhibiting ROCK, a RHOA effector and known RAC1 antagonist, reversed ibuprofen effects on migrating mouse ENCDC in culture. Ibuprofen also inhibited colonization of Ret+/− mouse bowel by ENCDC in vivo and dramatically reduced bowel colonization by chick ENCDC in culture. Interestingly, ibuprofen did not affect ENCDC migration until after at least three hours of exposure. Furthermore, mice deficient in Ptgs1 (COX 1) and Ptgs2 (COX 2) had normal bowel colonization by ENCDC and normal ENCDC migration in vitro suggesting COX-independent effects. Consistent with selective and strain specific effects on ENCDC, ibuprofen did not affect migration of gut mesenchymal cells, NIH3T3, or WT C57BL/6 ENCDC, and did not affect dorsal root ganglion cell precursor migration in zebrafish. Thus, ibuprofen inhibits ENCDC migration in vitro and bowel colonization by ENCDC in vivo in zebrafish, mouse and chick, but there are cell type and strain specific responses. These data raise concern that ibuprofen may increase Hirschsprung disease risk in some genetically susceptible children.

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Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease

Cited by 36 publications

References 18 publications

Detection of autophagy in Hirschsprung’s disease

Detection of autophagy in Hirschsprung’s disease

ICAM1K469E Polymorphism Effect in Gastroschisis Patients

Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse

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