# frizzled 5 mutant zebrafish are genetically sensitised to developing microphthalmia and coloboma

## TL;DR

This study shows that zebrafish lacking FZD5 develop normal eyes but are more likely to have eye defects when other genes are also disrupted, similar to some human conditions.

## Contribution

The study identifies aamp as a new gene involved in eye development and shows that FZD5 mutants are genetically sensitized to eye malformations.

## Key findings

- Zebrafish fzd5 mutants develop normal eyes without additional genetic disruption.
- Fzd5 mutants become sensitized to eye defects when other ocular genes are disrupted.
- The gene aamp was identified as a novel contributor to eye morphogenesis.

## Abstract

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.

Summary: This study provides insight into the mechanisms leading to eye malformation in fzd5 mutants and highlights the importance of considering multiple genetic defects when searching for the molecular aetiology of ocular malformations in humans.