Journal article
The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes
JCI insight, Vol.8(11), e168836
06/08/2023
DOI: 10.1172/jci.insight.168836
PMCID: PMC10393236
PMID: 37104040
Abstract
DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 genome editing in mice to recreate a human missense variant identified in patients with mild PCD and a second, frameshift-null deletion in
Dnaaf5
. Litters with
Dnaaf5
heteroallelic variants showed distinct missense and null gene dosage effects. Homozygosity for the null
Dnaaf5
alleles was embryonic lethal. Compound heterozygous animals with the missense and null alleles showed severe disease manifesting as hydrocephalus and early lethality. However, animals homozygous for the missense mutation had improved survival, with partially preserved cilia function and motor assembly observed by ultrastructure analysis. Notably, the same variant alleles exhibited divergent cilia function across different multiciliated tissues. Proteomic analysis of isolated airway cilia from mutant mice revealed reduction in some axonemal regulatory and structural proteins not previously reported in
DNAAF5
variants. Transcriptional analysis of mouse and human mutant cells showed increased expression of genes coding for axonemal proteins. These findings suggest allele-specific and tissue-specific molecular requirements for cilia motor assembly that may affect disease phenotypes and clinical trajectory in motile ciliopathies.
Details
- Title: Subtitle
- The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes
- Creators
- Amjad Horani - Washington University in St. Louis School of MedicineDeepesh Kumar Gupta - Washington University in St. Louis School of MedicineJian Xu - University of EdinburghHuihui Xu - Washington University in St. Louis School of MedicineLis del Carmen Puga-Molina - University of EdinburghCelia M. Santi - University of EdinburghSruthi Ramagiri - Washington University in St. LouisSteven K. Brennan - Washington University in St. Louis School of MedicineJiehong Pan - University of EdinburghJeffrey R. Koenitzer - University of EdinburghTao Huang - University of EdinburghRachael M. Hyland - Washington University in St. Louis School of MedicineSean P. Gunsten - University of EdinburghShin-Cheng Tzeng - University of EdinburghJennifer M. Strahle - Washington University in St. LouisPleasantine Mill - MRC Institute of Genetics and Molecular MedicineMoe R. Mahjoub - University of EdinburghSusan K. Dutcher - Washington University in St. LouisSteven L. Brody - University of Edinburgh
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.8(11), e168836
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.168836
- PMID
- 37104040
- PMCID
- PMC10393236
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- DBI-1827534 / ; FR-2021-933 / ; NS110793,HL146601,HL128370 / ;
- Language
- English
- Date published
- 06/08/2023
- Academic Unit
- Stead Family Department of Pediatrics; Neonatology
- Record Identifier
- 9984701656802771
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