Mutations in GAS8, a Gene Encoding a Nexin-Dynein Regulatory Complex Subunit, Cause Primary Ciliary Dyskinesia with Axonemal Disorganization.
Primary ciliary dyskinesia (PCD) is an autosomal recessive disease characterized by chronic respiratory infections of the upper and lower airways, hypofertility, and, in approximately half of the cases, situs inversus. This complex phenotype results from defects in motile cilia and sperm flagella. Among the numerous genes involved in PCD, very few-including CCDC39 and CCDC40-carry mutations that lead to a disorganization of ciliary axonemes with microtubule misalignment. Focusing on this particular phenotype, we identified bi-allelic loss-of-function mutations in GAS8, a gene that encodes a subunit of the nexin-dynein regulatory complex (N-DRC) orthologous to DRC4 of the flagellated alga Chlamydomonas reinhardtii. Unlike the majority of PCD patients, individuals with GAS8 mutations have motile cilia, which, as documented by high-speed videomicroscopy, display a subtle beating pattern defect characterized by slightly reduced bending amplitude. Immunofluorescence studies performed on patients' respiratory cilia revealed that GAS8 is not required for the proper expression of CCDC39 and CCDC40. Rather, mutations in GAS8 affect the subcellular localization of another N-DRC subunit called DRC3. Overall, this study, which identifies GAS8 as a PCD gene, unveils the key importance of the corresponding protein in N-DRC integrity and in the proper alignment of axonemal microtubules in humans.
Institut National de la Santé Et de la Recherche Médicale (INSERM), UMR_S933, Sorbonne Universités, UPMC Univ Paris 06, Paris, F-75012, France.
Ludovic
L
Jeanson
Institut National de la Santé Et de la Recherche Médicale (INSERM), UMR_S933, Sorbonne Universités, UPMC Univ Paris 06, Paris, F-75012, France.
Lucie
L
Thomas
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Génétique et Embryologie Médicales, Paris, F-75012, France.
Bruno
B
Copin
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Intercommunal et Groupe Hospitalier Henri Mondor - Albert Chenevier, Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, Créteil, F-94000, France.
André
A
Coste
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Necker, Service de Pneumo-Allergologie Pédiatrique, Paris, F-75015, France.
Isabelle
I
Sermet-Gaudelus
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Génétique et Embryologie Médicales, Paris, F-75012, France.
Florence
F
Dastot-Le Moal
Institut National de la Santé Et de la Recherche Médicale (INSERM), UMR_S933, Sorbonne Universités, UPMC Univ Paris 06, Paris, F-75012, France.
Philippe
P
Duquesnoy
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Génétique et Embryologie Médicales, Paris, F-75012, France.
Guy
G
Montantin
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Génétique et Embryologie Médicales, Paris, F-75012, France.
Nathalie
N
Collot
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Génétique et Embryologie Médicales, Paris, F-75012, France.
Sylvie
S
Tissier
Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Maxillo-Faciale, Le Kremlin-Bicêtre, F-94275, France.
Jean-François
JF
Papon
Institut National de la Santé Et de la Recherche Médicale (INSERM), UMR_S933, Sorbonne Universités, UPMC Univ Paris 06, Paris, F-75012, France.|Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Pneumologie Pédiatrique, Centre National de Référence des Maladies Respiratoires Rares, Paris, F-75012, France.
Annick
A
Clement
Institut National de la Santé Et de la Recherche Médicale (INSERM), UMR_S955, Equipe 13, Univ Paris Est, Créteil, F-94000, France.
Bruno
B
Louis
Institut National de la Santé Et de la Recherche Médicale (INSERM), UMR_S933, Sorbonne Universités, UPMC Univ Paris 06, Paris, F-75012, France.|Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Génétique et Embryologie Médicales, Paris, F-75012, France.
Estelle
E
Escudier
Institut National de la Santé Et de la Recherche Médicale (INSERM), UMR_S933, Sorbonne Universités, UPMC Univ Paris 06, Paris, F-75012, France.|Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Génétique et Embryologie Médicales, Paris, F-75012, France.
Serge
S
Amselem
Institut National de la Santé Et de la Recherche Médicale (INSERM), UMR_S933, Sorbonne Universités, UPMC Univ Paris 06, Paris, F-75012, France.|Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Service de Génétique et Embryologie Médicales, Paris, F-75012, France.
Marie
M
Legendre
D000328:Adult; D054468:Axoneme / Q000473:pathology*; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
D003598:Cytoskeletal Proteins; C115742:GAS8 protein, human; D009363:Neoplasm Proteins
GAS8; motile cilia; nexin-dynein regulatory complex; primary ciliary dyskinesia