Loss-of-function mutations in the human ortholog of Chlamydomonas reinhardtii ODA7 disrupt dynein arm assembly and cause primary ciliary dyskinesia.
Cilia and flagella are evolutionarily conserved structures that play various physiological roles in diverse cell types. Defects in motile cilia result in primary ciliary dyskinesia (PCD), the most prominent ciliopathy, characterized by the association of respiratory symptoms, male infertility, and, in nearly 50% of cases, situs inversus. So far, most identified disease-causing mutations involve genes encoding various ciliary components, such those belonging to the dynein arms that are essential for ciliary motion. Following a candidate-gene approach based on data from a mutant strain of the biflagellated alga Chlamydomonas reinhardtii carrying an ODA7 defect, we identified four families with a PCD phenotype characterized by the absence of both dynein arms and loss-of-function mutations in the human orthologous gene called LRRC50. Functional analyses performed in Chlamydomonas reinhardtii and in another flagellated protist, Trypanosoma brucei, support a key role for LRRC50, a member of the leucine-rich-repeat superfamily, in cytoplasmic preassembly of dynein arms.
Duquesnoy
Philippe
P
Institut National de Santé et de Recherche Médicale (INSERM) U.933, Université Pierre et Marie Curie-Paris 6 and Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, 75571 Paris cedex 12, France.
Escudier
Estelle
E
Vincensini
Laetitia
L
Freshour
Judy
J
Bridoux
Anne-Marie
AM
Coste
André
A
Deschildre
Antoine
A
de Blic
Jacques
J
Legendre
Marie
M
Montantin
Guy
G
Tenreiro
Henrique
H
Vojtek
Anne-Marie
AM
Loussert
Céline
C
Clément
Annick
A
Escalier
Denise
D
Bastin
Philippe
P
Mitchell
David R
DR
Amselem
Serge
S
D000595:Amino Acid Sequence; D016825:Chlamydomonas reinhardtii / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D004398:Dyneins / Q000235:genetics*; D005260:Female; D005407:Flagella / Q000378:metabolism; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014346:Trypanosoma brucei brucei / Q000378:metabolism
C546358:DNAAF1 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; D004398:Dyneins