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NRG1 variant effects in patients with Hirschsprung disease

Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 (NRG1) gene have been implicated in some cases of intestinal aganglionosis. | Gunadi et al. BMC Pediatrics 2018 18 292 https doi.org 10.1186 s12887-018-1265-x RESEARCH ARTICLE Open Access NRG1 variant effects in patients with Hirschsprung disease Gunadi1 Nova Yuli Prasetyo Budi1 Raman Sethi2 3 Aditya Rifqi Fauzi1 Alvin Santoso Kalim1 Taufik Indrawan1 Kristy Iskandar4 Akhmad Makhmudi1 Indra Adrianto5 and Lai Poh San2 3 Abstract Background Hirschsprung disease HSCR is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 NRG1 gene have been implicated in some cases of intestinal aganglionosis. This study aims to investigate the contribution of the NRG1 gene to HSCR development in an Indonesian population. Methods We analyzed the entire coding region of the NRG1 gene in 54 histopathologically diagnosed HSCR patients. Results All patients were sporadic non-syndromic HSCR with 53 54 98 short-segment and 1 54 2 long-segment patients. NRG1 gene analysis identified one rare variant c.397G C p.V133 L and three common variants rs7834206 rs3735774 and rs75155858. The p.V133 L variant was predicted to reside within a region of high mammalian conservation overlapping with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and potentially altering the AP-4_2 BDP1_disc3 Egr-1_known1 Egr-1_known4 HEN1_2 transcription factor binding motifs. This p.V133 L variant was absent in 92 non-HSCR controls. Furthermore the rs7834206 polymorphism was associated with HSCR by case-control analysis p 0.037 . Conclusions This study is the first report of a NRG1 rare variant associated with HSCR patients of South-East Asian ancestry and provides further insights into the contribution of NRG1 in the molecular genetic pathogenesis of HSCR. Keywords Hirschsprung disease Indonesia NRG1 variant Transcription factor binding motif Background Hirschsprung disease HSCR a heterogeneous genetic disorder is characterized by