2. Academic Validation
  3. Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms

Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms

  • Hum Mutat. 2013 Mar;34(3):462-72. doi: 10.1002/humu.22261.
Dinu Antony 1,  Anita Becker-Heck,  Maimoona A Zariwala,  Miriam Schmidts,  Alexandros Onoufriadis,  Mitra Forouhan,  Robert Wilson,  Theresa Taylor-Cox,  Ann Dewar,  Claire Jackson,  Patricia Goggin,  Niki T Loges,  Heike Olbrich,  Martine Jaspers,  Mark Jorissen,  Margaret W Leigh,  Whitney E Wolf,  M Leigh Anne Daniels,  Peadar G Noone,  Thomas W Ferkol,  Scott D Sagel,  Margaret Rosenfeld,  Andrew Rutman,  Abhijit Dixit,  Christopher O'Callaghan,  Jane S Lucas,  Claire Hogg,  Peter J Scambler,  Richard D Emes,  Uk10k,  Eddie M K Chung,  Amelia Shoemark,  Michael R Knowles,  Heymut Omran,  Hannah M Mitchison
Affiliations

Affiliation

  • 1 Molecular Medicine Unit and Birth Defects Research Centre, University College London (UCL) Institute of Child Health, London, UK.
PMID: 23255504 DOI: 10.1002/humu.22261
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."

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