The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD.
Department of Pediatrics, University Hospital Freiburg, Freiburg, Germany.
Anita
A
Becker-Heck
Irene E
IE
Zohn
Noriko
N
Okabe
Andrew
A
Pollock
Kari Baker
KB
Lenhart
Jessica
J
Sullivan-Brown
Jason
J
McSheene
Niki T
NT
Loges
Heike
H
Olbrich
Karsten
K
Haeffner
Manfred
M
Fliegauf
Judith
J
Horvath
Richard
R
Reinhardt
Kim G
KG
Nielsen
June K
JK
Marthin
Gyorgy
G
Baktai
Kathryn V
KV
Anderson
Robert
R
Geisler
Lee
L
Niswander
Heymut
H
Omran
Rebecca D
RD
Burdine
D000818:Animals; D002923:Cilia / Q000235:genetics; D002925:Ciliary Motility Disorders / Q000235:genetics*; D004398:Dyneins / Q000235:genetics; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012857:Situs Inversus / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics
C556028:CCDC40 protein, human; C556027:CCDC40 protein, mouse; C556029:CCDC40 protein, zebrafish; D011506:Proteins; D029961:Zebrafish Proteins; D004398:Dyneins