<i>frizzled 5</i> mutant zebrafish are genetically sensitised to developing microphthalmia and coloboma

Microphthalmia and coloboma are structural malformations of the eyes that arise from defective morphogenesis and are among the most severe defects associated with paediatric blindness. Frizzled class receptor 5 (FZD5) is a Wnt receptor expressed in the developing eye, and individuals with variants in FZD5 exhibit microphthalmia/coloboma, supporting a role for this receptor in human eye formation. Here, we show that zebrafish fzd5 mutants homozygous for complete loss-of-function or predicted dominant-negative alleles display no obvious eye defects during embryogenesis. Rather, they develop eye defects comparable to those described in humans only upon simultaneous abrogation of additional genes associated with ocular malformations. Thus, eye development can occur normally in the absence of Fzd5 in zebrafish, but mutants are sensitised to developing eye malformations. By exploiting the sensitised nature of the fzd5 mutants, we further identified angio-associated migratory cell protein (aamp) as a novel gene involved in eye morphogenesis. Overall, our study confirms the importance of considering multiple genetic contributions when searching for the molecular aetiology of ocular malformations in humans.