Skewed X-chromosome inactivation drives the proportion of DNAAF6-defective airway motile cilia and variable expressivity in primary ciliary dyskinesia - Maladies génétiques d'expression pédiatrique Accéder directement au contenu
Poster De Conférence Année : 2024

Skewed X-chromosome inactivation drives the proportion of DNAAF6-defective airway motile cilia and variable expressivity in primary ciliary dyskinesia

Lucie Thomas
Guy Montantin
Sylvie Tissier
Sandra Chantot-Bastaraud
Jean-Pierre Siffroi

Résumé

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 6 mothers of male patients with DNAAF6-related PCD were determined by DNA-methylation studies and compared to 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 20-50% - normal ciliated airway cells sufficed to avoid severe PCD, a result paving the way for gene therapy.
Fichier principal
Vignette du fichier
MarieLEGENDRE_P05.004.D_V4.pdf (1.54 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)

Dates et versions

inserm-04614713 , version 1 (17-06-2024)

Identifiants

  • HAL Id : inserm-04614713 , version 1

Citer

Lucie Thomas, Laurence Cuisset, Jean-François Papon, Aline Tamalet, Isabelle Pin, et al.. Skewed X-chromosome inactivation drives the proportion of DNAAF6-defective airway motile cilia and variable expressivity in primary ciliary dyskinesia. The European Society of Human Genetics, Jun 2024, Berlin (DE), Germany. ⟨inserm-04614713⟩
0 Consultations
0 Téléchargements

Partager

Gmail Mastodon Facebook X LinkedIn More