Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia

TY - JOUR

T1 - Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia

AU - Onoufriadis, Alexandros

AU - Paff, Tamara

AU - Antony, Dinu

AU - Shoemark, Amelia

AU - Micha, Dimitra

AU - Kuyt, Bertus

AU - Schmidts, Miriam

AU - Petridi, Stavroula

AU - Dankert-Roelse, Jeanette E.

AU - Haarman, Eric G.

AU - Daniels, Johannes M.A.

AU - Emes, Richard D.

AU - Wilson, Robert

AU - Hogg, Claire

AU - Scambler, Peter J.

AU - Chung, Eddie M.K.

AU - Pals, Gerard

AU - Mitchison, Hannah M.

PY - 2013/1/10

Y1 - 2013/1/10

N2 - Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right laterality disturbances, usually as a result of loss of the outer dynein arms (ODAs) that power cilia/flagella beating. Here, we identify loss-of-function mutations in CCDC114 causing PCD with laterality malformations involving complex heart defects. CCDC114 is homologous to DCC2, an ODA microtubule-docking complex component of the biflagellate alga Chlamydomonas. We show that CCDC114 localizes along the entire length of human cilia and that its deficiency causes a complete absence of ciliary ODAs, resulting in immotile cilia. Thus, CCDC114 is an essential ciliary protein required for microtubular attachment of ODAs in the axoneme. Fertility is apparently not greatly affected by CCDC114 deficiency, and qPCR shows that this may explained by low transcript expression in testis compared to ciliated respiratory epithelium. One CCDC114 mutation, c.742G>A, dating back to at least the 1400s, presents an important diagnostic and therapeutic target in the isolated Dutch Volendam population.

AB - Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right laterality disturbances, usually as a result of loss of the outer dynein arms (ODAs) that power cilia/flagella beating. Here, we identify loss-of-function mutations in CCDC114 causing PCD with laterality malformations involving complex heart defects. CCDC114 is homologous to DCC2, an ODA microtubule-docking complex component of the biflagellate alga Chlamydomonas. We show that CCDC114 localizes along the entire length of human cilia and that its deficiency causes a complete absence of ciliary ODAs, resulting in immotile cilia. Thus, CCDC114 is an essential ciliary protein required for microtubular attachment of ODAs in the axoneme. Fertility is apparently not greatly affected by CCDC114 deficiency, and qPCR shows that this may explained by low transcript expression in testis compared to ciliated respiratory epithelium. One CCDC114 mutation, c.742G>A, dating back to at least the 1400s, presents an important diagnostic and therapeutic target in the isolated Dutch Volendam population.

UR - https://www.scopus.com/pages/publications/84872342461

U2 - 10.1016/j.ajhg.2012.11.002

DO - 10.1016/j.ajhg.2012.11.002

M3 - Article

C2 - 23261303

AN - SCOPUS:84872342461

SN - 0002-9297

VL - 92

SP - 88

EP - 98

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -