Mutations in the NRG1 gene are associated with Hirschsprung disease

Abstract

Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (NRG1; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the NRG1 exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239fsX10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of NRG1 RVs in HSCR patients (p = 0.008). We show here that not only common, but also rare variants of the NRG1 gene contribute to HSCR. This strengthens the role of NRG1.

The expression and localization of neuregulin-1 (Nrg1) in the gastrointestinal system of the rhesus monkey

“…Here, Nrg1 and ErbB2/ErbB4 receptors were sparsely and weakly expressed in the esophagus and colon tissues, which may suggest that they are not functionally vital in these tissues. However, both common and rare variants of the NRG1 gene have been reported to contribute to Hirschsprung disease (HSCR, congenital colon aganglionosis), a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS) [20].…”

Involvement of DNMT3B in the pathogenesis of Hirschsprung disease and its possible role as a regulator of neurogenesis in the human enteric nervous system

“…[2][3][4][5][6][7][8][9][10][11] HSCR is regarded as a disorder with complex genetic basis. The contribution of different mutational events within several loci acting in an additive manner is usually involved in the development of this disease.…”

Hedgehog and Notch Signaling in Enteric Nervous System Development

“…HSCR exhibits multifactorial modes of inheritance and more than 14 genes have been identified associated with HSCR, but mutations in these genes are of incomplete penetrance and account for only 50% of the familial and up to 20% of the sporadic cases [13]. More recently, genome-wide association study (GWAS) conducted on HSCR patients has uncovered many more new disease loci and provided valuable insights into the contribution of structural variants to HSCR [14,15,16,17]. Intriguingly, many of these genetic variants/mutations are found in genes such as RET, NEUREGULIN 1 and 3 , PATCHED1 and DELTA-LIKE3 that regulate the proliferation, migration or differentiation of enteric NCCs, highlighting the relevance of these genes in ENS development and HSCR pathogenesis.…”