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AB071. Semaphorin 3D impact in Indonesian Hirschsprung patients

ABSTRACT: Background Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines, results in functional bowel obstruction in children. Recently, Semaphorin 3D (SEMA3D) gene has been implicated in the pathogenesis of intestinal ganglionosis. We aimed to conduct a mutation analysis of SEMA3D gene in HSCR patients in Indonesia, a genetically distinct group within Asia. Methods We ascertained 40 patients with HSCR of whom 27 and 13 were males and females, respectively. Subsequently, we performed direct sequencing to clarify the contribution of SEMA3D gene to HSCR development. Results All patients were sporadic HSCR with degree of aganglionosis as follows: short-segment in 39/40 (98%) patients and long-segment in 1/40 (2%) patients. Transanal endorectal pull-through (TEPT) has been the most common definitive surgery (54%), followed by Duhamel (21%), and Soave (14%). Mutation analysis of SEMA3D gene showed no rare variant, but one common variant in exon 17, rs7800072. The risk allele frequency at rs7800072 (C) among HSCR patients were 0.52. Conclusions This result implies that the SEMA3D gene may not have an effect in the molecular pathogenesis of HSCR, particularly in Indonesia. This study is the first report of SEMA3D gene in Asian ancestry. Further study with multicenter and a larger number of samples is necessary to clarify the results.

SUBMITTER: Iskandar K

PROVIDER: S-EPMC5641688 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Project description:Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic colon segment and functional intestinal obstruction. The RET proto-oncogene is the major gene associated to HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In addition, many other genes have been described to be associated with this pathology, including the semaphorins class III genes SEMA3A (7p12.1) and SEMA3D (7q21.11) through SNP array analyses and by next-generation sequencing technologies. Semaphorins are guidance cues for developing neurons implicated in the axonal projections and in the determination of the migratory pathway for neural-crest derived neural precursors during enteric nervous system development. In addition, it has been described that increased SEMA3A expression may be a risk factor for HSCR through the upregulation of the gene in the aganglionic smooth muscle layer of the colon in HSCR patients. Here we present the results of a comprehensive analysis of SEMA3A and SEMA3D in a series of 200 Spanish HSCR patients by the mutational screening of its coding sequence, which has led to find a number of potentially deleterious variants. RET mutations have been also detected in some of those patients carrying SEMAs variants. We have evaluated the A131T-SEMA3A, S598G-SEMA3A and E198K-SEMA3D mutations using colon tissue sections of these patients by immunohistochemistry. All mutants presented increased protein expression in smooth muscle layer of ganglionic segments. Moreover, A131T-SEMA3A also maintained higher protein levels in the aganglionic muscle layers. These findings strongly suggest that these mutants have a pathogenic effect on the disease. Furthermore, because of their coexistence with RET mutations, our data substantiate the additive genetic model proposed for this rare disorder and further support the association of SEMAs genes with HSCR.

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AB071. Semaphorin 3D impact in Indonesian Hirschsprung patients

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