Structural variation in a novel zinc finger protein and investigation of its role in Hirschsprung disease

Abstract

Zinc finger transcription factors play essential roles in neural crest cell development. Even subtle disruptions of the function of these genes could contribute significantly to complex developmental phenotypes such as the multigenic disorder Hirschsprung disease (HSCR), a congenital failure of enteric neurogenesis. Although germline mutations in the RET proto‐oncogene are the most common cause of familial disease, at least 8 genes including transcription factors have been implicated in sporadic HSCR to date. Thus, a further group of candidate genes are those involved in regulating expression of known HSCR genes. In this study, we have characterized the ZNF358 zinc finger gene, a human orthologue of the mouse gene zfend, which is expressed in early developmental stages in the gut and in the neural folds at the time of neural crest differentiation. ZNF358 represents a putative transcription factor with DNA binding activity confered by 9 Cys2His2 zinc fingers. Although we did not detect disease associated mutations in a panel of HSCR patients, we did identify a novel variable sequence within the coding region of ZNF358 that would result in a deletion of nine amino acids from a polyalanine domain. Our molecular model suggests that this variant could alter protein tertiary structure and the ability of ZNF358 to regulate transcription. Together, our data suggest that, while ZNF358 may be involved in the regulation of genes such as those necessary for development or differentiation of neural crest cells, it does not play an obvious role in HSCR.

FOXE1 Polyalanine Tract Length Polymorphism in Patients with Thyroid Hemiagenesis and Subjects with Normal Thyroid

“…On the other hand, polyalanine tract contractions have not been involved with certainty in the etiopathogenesis of human diseases [16,17,18]. …”