Intronic RET gene variants in Down syndrome-associated Hirschsprung disease in an African population.
BACKGROUND
Clinical association between Hirschsprung disease (HD) and Down syndrome (DS) is well established. RET promoter and intron 1 variations have been shown to interfere with RET function, increasing the risk of HD pathogenesis. The intronic single-nucleotide polymorphism 2 (SNP2 [rs2435357]) has been associated with DS-associated HD (DS-HD). This study focuses on variations of specific RET intron, 1 SNPs (viz, SNP1 [rs2506004] and SNP2 [rs2435357]) in DS-HD.


METHODS
DNA was extracted from paraffin-embedded tissue samples and whole blood in 14 patients with DS with histologically proven HD. Polymerase chain reaction products of RET intron 1 were screened for genetic variation and matched to DS and controls from the general population.


RESULTS
Thirty-seven blood and/or tissue from 14 patients with DS-HD were investigated. RET intronic variations (SNP1 [rs2506004] or SNP2 [rs2435357]) were detected in all patients. SNP1 was detected in all patients, was heterozygous in 9, and homozygous in 5 samples (all aganglionic and 1 total colonic aganglionosis). SNP2 was absent in 6 patients, heterozygous in 6, and homozygous in 3. Three DS controls had a heterozygous SNP1. Homozygous intronic SNP RET variations were related to aganglionic tissue but not normally ganglionated or transitional zone from the same individual.


CONCLUSIONS
Potential disease-related RET mutations were identified in the intron region in 80% of patients with DS-HD investigated, suggesting a causal relationship. The presence of a homozygous form in the aganglionic tissue probably represents a somatic mutation, which suggests local microenvironmental factors in HD pathogenesis.
Division of Paediatric Surgery, Faculty of Medicine, University of Stellenbosch, P.O. Box 19063, 7505, Tygerberg, South Africa. swm@sun.ac.za
Samuel W
SW
Moore
Monique G
MG
Zaahl
D044383:Black People / Q000235:genetics; D015984:Causality; D015897:Comorbidity; D004252:DNA Mutational Analysis; D004314:Down Syndrome / Q000453:epidemiology*; D005060:Europe / Q000208:ethnology; D005260:Female; D005838:Genotype; D006627:Hirschsprung Disease / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D007422:Intestines / Q000473:pathology; D007438:Introns / Q000235:genetics*; D008297:Male; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011519:Proto-Oncogenes; D013019:South Africa / Q000453:epidemiology; D044465:White People / Q000235:genetics
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human