title: Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms.
abstract: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed "radial spoke defect." We sequenced CCDC39 and CCDC40 in 54 "radial spoke defect" families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice, and frameshift predicting early protein truncation, which suggests this defect is caused by "null" alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganization and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as "IDA and microtubular disorganisation defect," rather than "radial spoke defect."
authors.affiliation: Molecular Medicine Unit and Birth Defects Research Centre, University College London (UCL) Institute of Child Health, London, UK.
authors.forename: Dinu
authors.initials: D
authors.lastname: Antony
authors.forename: Anita
authors.initials: A
authors.lastname: Becker-Heck
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.forename: Alexandros
authors.initials: A
authors.lastname: Onoufriadis
authors.forename: Mitra
authors.initials: M
authors.lastname: Forouhan
authors.forename: Robert
authors.initials: R
authors.lastname: Wilson
authors.forename: Theresa
authors.initials: T
authors.lastname: Taylor-Cox
authors.forename: Ann
authors.initials: A
authors.lastname: Dewar
authors.forename: Claire
authors.initials: C
authors.lastname: Jackson
authors.forename: Patricia
authors.initials: P
authors.lastname: Goggin
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Martine
authors.initials: M
authors.lastname: Jaspers
authors.forename: Mark
authors.initials: M
authors.lastname: Jorissen
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
authors.forename: Whitney E
authors.initials: WE
authors.lastname: Wolf
authors.forename: M Leigh Anne
authors.initials: ML
authors.lastname: Daniels
authors.forename: Peadar G
authors.initials: PG
authors.lastname: Noone
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Ferkol
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.forename: Andrew
authors.initials: A
authors.lastname: Rutman
authors.forename: Abhijit
authors.initials: A
authors.lastname: Dixit
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Callaghan
authors.forename: Jane S
authors.initials: JS
authors.lastname: Lucas
authors.forename: Claire
authors.initials: C
authors.lastname: Hogg
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Richard D
authors.initials: RD
authors.lastname: Emes
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.forename: Amelia
authors.initials: A
authors.lastname: Shoemark
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
mesh_terms: D000483:Alleles; D054468:Axoneme / Q000235:genetics* / Q000473:pathology; D002923:Cilia / Q000235:genetics / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D004398:Dyneins / Q000235:genetics*; D059472:Exome; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*
chemical_list: C556026:CCDC39 protein, human; C556028:CCDC40 protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins; D004398:Dyneins