Etiology and functional validation of gastrointestinal motility dysfunction in a zebrafish model of CHARGE syndrome

Abstract

CHARGE syndrome is linked to autosomal-dominant mutations in the CHD7 gene and results in a number of physiological and structural abnormalities, including heart defects, hearing and vision loss, and gastrointestinal (GI) problems. Of these challenges, GI problems have a profound impact throughout an individual's life, resulting in increased morbidity and mortality. A homolog of CHD7 has been identified in the zebrafish, the loss of which recapitulates many of the features of the human disease. Using a morpholino chd7 knockdown model complemented by a chd7 null mutant zebrafish line, we examined GI structure, innervation, and motility in larval zebrafish. Loss of chd7 resulted in physically smaller GI tracts with normal epithelial and muscular histology, but decreased and disorganized vagal projections, particularly in the foregut. chd7 morphant larvae had significantly less ability to empty their GI tract of gavaged fluorescent beads, and this condition was only minimally improved by the prokinetic agents, domperidone and erythromycin, in keeping with mixed responses to these agents in patients with CHARGE syndrome. The conserved genetics and transparency of the zebrafish have provided new insights into the consequences of chd7 gene dysfunction on the GI system and cranial nerve patterning. These findings highlight the opportunity of the zebrafish to serve as a preclinical model for studying compounds that may improve GI motility in individuals with CHARGE syndrome.

Zebrafish Models of Neurodevelopmental Disorders: Past, Present, and Future

“…For example, both mutants and morphants of CHD7 , the gene that is associated with most cases of CHARGE syndrome, display pericardial edema and cardiac abnormalities, consistent with cardiac abnormalities found in affected individuals (Patten et al, 2012; Balow et al, 2013; Cloney et al, 2018). In addition, chd7 mutants (and morphants) display decreased GI emptying (Cloney et al, 2018), while chd8 morphants showed reduced GI motility (Bernier et al, 2014), which may be relevant to GI symptoms in individuals carrying mutations in these genes. Further, zebrafish models of tuberous sclerosis complex, including tsc1a morphants and tsc2 mutants, display increased TORC activity (DiBella et al, 2009; Kim et al, 2011).…”

Chromatin remodeler Chd7 regulates photoreceptor development and outer segment length

“…The CRISPR mutant line used in our study was also previously reported to display gastrointestinal motility defects in both heterozygous and homozygous mutants. Taken together, these results suggest that loss of Chd7 in zebrafish results in haploinsufficient phenotypes similar to human CHARGE syndrome (Cloney et al, 2018), and the eye phenotypes further establish zebrafish as a model to investigate the pathogenesis of CHARGE syndrome-associated ocular defects.…”

New Feeding Assessment Scale for individuals with genetic syndromes: Validity and reliability in the CHARGE syndrome population

“…Cranial nerve IX, X, XI and XII all play essential roles in the sensory and motor innervation of the tongue, pharynx and larynx, contributing to the manipulation of food, formation of food bolus, and initiation of swallowing. Innervation may be dysfunctional along the entire GI tract, with reduced enteric system innervation and gut motility having been reported in zebrafish models of CHARGE syndrome 30 . A higher percentage of cleft palates have been previously reported in individuals with CHARGE syndrome who have the problematic feeding behaviours of pocketing food in cheeks and overstuffing food into their mouth, compared to the general CHARGE syndrome population 21 .…”