Infantile hypertrophic pyloric stenosis: evaluation of three positional candidate genes, TRPC1, TRPC5 and TRPC6, by association analysis and re-sequencing

Abstract

Infantile hypertrophic pyloric stenosis (IHPS) is the most common inherited form of gastrointestinal obstruction in infancy with a striking male preponderance. Infants present with vomiting due to gastric outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. Two loci specific to extended pedigrees displaying autosomal dominant inheritance have been identified. A genome scan identified loci on chromosomes 11q14-q22 and Xq23-q24 which are predicted to be responsible for a subset of smaller families with IHPS demonstrating non-Mendelian inheritance. The two linked chromosomal regions both harbour functional candidate genes which are members of the canonical transient receptor potential (TRPC) family of ion channels. Both TRPC5 (Xq23-q24) and TRPC6 (11q14-q22) have a potential role in smooth muscle control and hypertrophy. Here, we report suggestive evidence for a third locus on chromosome 3q12-q25 (Zmax = 2.7, p < 0.004), a region which harbours a third TRPC gene, TRPC1. Fine mapping of all three genes using a tagSNP approach and re-sequencing identified a SNP in the promoter region of TRPC6 and a missense variant in exon 4 of TRPC6 which may be putative causal variants.

Pyloric stenosis a 100 years after Ramstedt

“…The two linked chromosomal regions each harbour functional candidate genes that are members of the canonical transient receptor potential (TRPC) family of ion channels and have a potential role in smooth-muscle control and hypertrophy: TRPC6 and TRPC5. Further analysis provided suggestive evidence for a third locus on chromosome 3q12–q25, a region which harbours a third TRPC gene, TRPC1 12. Fine mapping of all three genes using a tagSNP approach and re-sequencing identified a SNP in the promoter region of TRPC6 and a missense variant in exon 4 of TRPC6 , which may be putative causal variants.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In Turkish children, three mutations and an intronic nucleotide substitution were described causing the sporadic form of this disease (Mir et al, 2012). A SNP in the promoter region of TRPC6 and a missense variant in exon 4 of TRPC6 might be putative causal gene variants for infantile hypertrophic pyloric stenosis (OMIM 179010) (Everett et al, 2009). Mutations in TRPC6 may also contribute to idiopathic pulmonary arterial hypertension (IPAH) , in which SNPs were described in a cohort of patients.…”

Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system

“…An implication of TRPC6 in human GI motor control is exemplified by the observation that a single nucleotide polymorphism in the promoter region of the TRPC6 gene and a missense variant in exon 4 of the TRPC6 gene may contribute to infantile hypertrophic pyloric stenosis (Everett et al, in press). TRPC6 appears to have a role in cancer development, given that there is a marked upregulation of TRPC6 expression in esophageal squamous cell carcinoma (Shi et al, 2009) and in epithelial cells of human gastric cancers (Cai et al, 2009).…”