SRY interference of normal regulation of the RET gene suggests a potential role of the Y-chromosome gene in sexual dimorphism in Hirschsprung disease.

[hirschsprung disease]

The Hirschsprung disease (HSCR ) is a complex congenital disorder , arising from abnormalities in enteric nervous system (ENS ) development . There is a gender disparity among the patients , with the male to female ratio as high as 5 : 1 . Loss -of-function mutations of HSCR genes and haploinsufficiency of their gene products are the primary pathogenic mechanisms for disease development . Recent studies identified over half of the HSCR disease susceptibility genes as targets for the sex-determining factor SRY , suggesting that this Y-encoded transcription factor could be involved in sexual dimorphism in HSCR . Among the SRY targets , the tyrosine kinase receptor RET represents the most important disease gene , whose mutations account for half of the familial and up to one -third of the sporadic forms of HSCR . RET is regulated by a distal and a proximal enhancer at its promoter , in which PAX 3 and NKX 2 -1 are the resident transcription factors respectively . We show that the SRY -box 10 (SOX 10 ) co -activator interacts and forms transcriptional complexes with PAX 3 and NKX 2 -1 in a sequence-independent manner and exacerbates their respective transactivation activities on the RET promoter . SRY competitively displaces SOX 10 in such transcription complexes and represses their regulatory functions on RET . Hence SRY could be a Y-located negative modifier of RET expression ; and if it is ectopically expressed during ENS development , such SRY repression could result in RET protein haploinsufficiency and promotion of HSCR development , thereby contributing to sexual dimorphism in HSCR .

Diseases
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Diseases presenting "haploinsufficiency of their gene products are the primary pathogenic mechanisms for disease development" symptom

hirschsprung disease

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