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Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants
Jun Wang1, Holly R Thomas1, Robert G Thompson1
1Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Disease Models & Mechanisms
|December 19, 2022
Summary
Mutations in transition zone (TZ) proteins cause distinct ciliopathies, but modifier genes influence phenotypes. Zebrafish models reveal tissue-specific TZ gene functions and complex, variable disease presentations, aiding identification of new cilia-associated genes.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- Ciliary transition zone (TZ) proteins are crucial for ciliopathies like Meckel, nephronophthisis, Joubert, and Bardet-Biedl syndromes.
- Distinct syndromes suggest varied TZ protein functions, yet single gene mutations can cause multiple syndromes, implying genetic modifiers.
Purpose of the Study:
- To investigate tissue-specific functions of TZ genes using zebrafish models.
- To explore the genetic basis of phenotypic variability in ciliopathies.
- To rapidly identify novel cilia-associated genes using CRISPR/Cas9 technology.
Main Methods:
- Comprehensive analysis of ten zebrafish TZ mutants (mks1, tmem216, tmem67, rpgrip1l, cc2d2a, b9d2, cep290, tctn1, nphp1, nphp4) and additional mutants (ift88, ift172).
- Phenotypic characterization of TZ mutants, including observation of variations within and across mutants.
- Application of multiple-guide CRISPR/Cas9 in F0 'crispant' embryos to identify ciliary phenotypes in candidate genes.
Main Results:
- Phenotypic variations among different TZ mutants support tissue-specific roles for these genes.
- Intra-mutant phenotypic variability and transient phenotypes were observed, mirroring complex human ciliopathies.
- CRISPR/Cas9 identified ciliary phenotypes in 11 novel cilia-associated gene candidates.
Conclusions:
- Zebrafish TZ mutants reveal complex gene functions and phenotypic variability in ciliopathies.
- Modifier genes likely influence ciliopathy phenotypes.
- CRISPR/Cas9 is an effective tool for rapid identification of genes involved in ciliary function.
