Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet–Biedl syndrome
2008
Facial recognition is central to the diagnosis of many syndromes, and
craniofacialpatterns may reflect common etiologies. In the pleiotropic
Bardet–Biedl syndrome(BBS), a primary
ciliopathywith
intraflagellar transportdysfunction, patients have a characteristic facial “gestalt” that dysmorphologists have found difficult to characterize. Here, we use dense surface modeling (DSM) to reveal that BBS patients and mouse mutants have mid-facial defects involving homologous
neural crest-derived structures shared by zebrafish
morphants. These defects of the
craniofacial(CF) skeleton arise from aberrant
cranial neural crestcell (NCC) migration. These effects are not confined to the
craniofacialregion, but vagal-derived NCCs fail to populate the
enteric nervous system, culminating in disordered gut motility. Furthermore,
morphantsdisplay hallmarks of disrupted
Sonic Hedgehog(Shh) signaling from which NCCs take positional cues. We propose a model whereby Bbs proteins modulate NCC migration, contributing to
craniofacialmorphogenesis and development of the
enteric nervous system. These migration defects also explain the association of
Hirschsprung's disease(HD) with BBS. Moreover, this is a previously undescribed method of using characterization of facial dysmorphology as a basis for investigating the pathomechanism of CF development in dysmorphic syndromes.
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