Rare Diseases Symptoms Automatic Extraction

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 PAX3 and NKX2-1 are the resident transcription factors respectively. We show that the SRY-box 10 (SOX10) co-activator interacts and forms transcriptional complexes with PAX3 and NKX2-1 in a sequence-independent manner and exacerbates their respective transactivation activities on the RET promoter. SRY competitively displaces SOX10 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 presenting "loss-of-function mutations" symptom

  • achondroplasia
  • alpha-thalassemia
  • aromatase deficiency
  • child syndrome
  • cowden syndrome
  • dystrophic epidermolysis bullosa
  • epidermolysis bullosa simplex
  • erythropoietic protoporphyria
  • esophageal adenocarcinoma
  • familial hypocalciuric hypercalcemia
  • harlequin ichthyosis
  • hirschsprung disease
  • kallmann syndrome
  • kindler syndrome
  • lamellar ichthyosis
  • neonatal adrenoleukodystrophy
  • pendred syndrome
  • werner syndrome
  • x-linked adrenoleukodystrophy

This symptom has already been validated