Article Text
Abstract
Background Primary ciliary dyskinesia (PCD) is a rare airway disorder caused by defective motile cilia. Only male patients have been reported with pathogenic mutations in X-linked DNAAF6, which result in the absence of ciliary dynein arms, whereas their heterozygous mothers are supposedly healthy. Our objective was to assess the possible clinical and ciliary consequences of X-chromosome inactivation (XCI) in these mothers.
Methods XCI patterns of six mothers of male patients with DNAAF6-related PCD were determined by DNA-methylation studies and compared with their clinical phenotype (6/6 mothers), as well as their ciliary phenotype (4/6 mothers), as assessed by immunofluorescence and high-speed videomicroscopy analyses. The mutated X chromosome was tracked to assess the percentage of cells with a normal inactivated DNAAF6 allele.
Results The mothers’ phenotypes ranged from absence of symptoms to mild/moderate or severe airway phenotypes, closely reflecting their XCI pattern. Analyses of the symptomatic mothers’ airway ciliated cells revealed the coexistence of normal cells and cells with immotile cilia lacking dynein arms, whose ratio closely mirrored their XCI pattern.
Conclusion This study highlights the importance of searching for heterozygous pathogenic DNAAF6 mutations in all female relatives of male PCD patients with a DNAAF6 defect, as well as in females consulting for mild chronic respiratory symptoms. Our results also demonstrate that about one-third—ranging from 20% to 50%—normal ciliated airway cells sufficed to avoid severe PCD, a result paving the way for gene therapy.
- X-Linked Genetic Diseases
- Respiratory Tract Diseases
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Footnotes
Contributors LT contributed in the study design, acquisition and analysis of data, and writing the manuscript. LC analysed methylation-sensitive digestion experiments and participated to the manuscript review. JFP was involved in the acquisition of clinical data, the follow-up of the investigated mothers and the nasal brushing samples. AT, IP, GT and AC were involved in the acquisition of clinical data and follow-up of the investigated mothers. RAT participated in clinical phenotyping of mothers. CF conducted all TEM experiments. GM, ST, PD, FDLM and BC performed genetic analyses. NC performed methylation-sensitive digestion experiments. BL developed and provided the HSVA software. SC conducted the acquisition and analysis of copy-number-variation data. RM was involved in TEM analyses and data interpretation. EE participated in the study conception and design, the interpretation of data and in writing and review the manuscript. SA was involved in the study conception, the analysis of the data, the redaction and the final approval of the manuscript. ML conceived the study and contributed to study design, participated to the analysis of the data, the redaction and final approval of the manuscript, and acts as a guarantor. All authors revised the manuscript and gave their final approval.
Funding This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Fondation pour la Recherche Médicale and the Legs Poix from the Chancellerie des Universités.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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