Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease

Abstract

In a study of a large family with history of HSCR, we identified variants in LRBA, RET, the gene encoding the RET ligand (GDNF), IHH, and a gene encoding a mediator of IHH signaling (GLI3). These variants altered functions of the gene products when expressed in cells and knockout of ihh reduced the number of enteric neurons in the zebrafish gut.

Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease

“…It has been reported that genetic factors and their regulatory mechanisms may play an important role in the development of HSCR (Bahrami et al, 2018; Sribudiani et al, 2018). To better understand the etiology and pathogenesis of HSCR, we compared the expression differences of mRNA in three pairs of colon tissues from HSCR ganglionic controls and aganglionic segments.…”

“…To better elucidate the molecular mechanisms underlying this disease, a large number of studies are devoted to the exploration of susceptibility genes and related cellular and molecular mechanisms. To date, mutations in approximately 20 genes have been identified in HSCR patients (Sribudiani et al, 2018). Among these, RET is considered the major susceptibility gene for HSCR disease.…”

“…Among these, RET is considered the major susceptibility gene for HSCR disease. In human, mutations in RET account for 50% of familial cases of HSCR and up to 35% of sporadic cases (Sribudiani et al, 2018). Moreover, approximately 5% of HSCR cases carry heterozygous mutations in EDN3, EDNRB and the endothelin converting enzyme ECE1 (Heanue and Pachnis, 2007; Bahrami et al, 2018).…”

What is new about the genetic background of Hirschsprung disease?

“…Classical linkage approaches were performed in multigenerational families and siblings with HSCR, to discern alleles and haplotypes linked to the disease. [8][9][10][11][12][13] Moreover, in vitro and/or in vivo assays have led to the identification of the genes involved in the onset of HSCR. 14 Within those genes, different receptors, ligands and transcription factors are encoded.…”

The advances of genetics research on Hirschsprung's disease

“…Lately, a targeted exome sequencing on a linkage interval 4q31.3–4q32.3 previously identified, coupled with a WES study identified several variants in LRBA , RET , GDNF , IHH , and GLI3 in a multigenerational Dutch family with history of HSCR. Further functional experiments showed that these variants disrupted the function of their encoded proteins, and knockdown of ihh in zebrafish significantly reduced the number of enteric neurons in the gut . In addition, a WGS study was conducted on 9 trios where the sporadic probands had L‐HSCR or TCA and harbored no rare coding variants affecting the function of RET and other known HSCR risk genes.…”