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Mutations in CCDC 39 and CCDC 40 are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms
Author(s) -
Antony Dinu,
BeckerHeck Anita,
Zariwala Maimoona A.,
Schmidts Miriam,
Onoufriadis Alexandros,
Forouhan Mitra,
Wilson Robert,
TaylorCox Theresa,
Dewar Ann,
Jackson Claire,
Goggin Patricia,
Loges Niki T.,
Olbrich Heike,
Jaspers Martine,
Jorissen Mark,
Leigh Margaret W.,
Wolf Whitney E.,
Daniels M. Leigh Anne,
Noone Peadar G.,
Ferkol Thomas W.,
Sagel Scott D.,
Rosenfeld Margaret,
Rutman Andrew,
Dixit Abhijit,
O'Callaghan Christopher,
Lucas Jane S.,
Hogg Claire,
Scambler Peter J.,
Emes Richard D.,
Chung Eddie M.K.,
Shoemark Amelia,
Knowles Michael R.,
Omran Heymut,
Mitchison Hannah M.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22261
Subject(s) - biology , primary ciliary dyskinesia , cilium , genetics , dynein , frameshift mutation , phenotype , motile cilium , microtubule , gene , philosophy , linguistics , bronchiectasis , lung
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 CCDC 39 and CCDC 40 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 CCDC 39 and 13 in CCDC 40 ). 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, CCDC 40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC 39 and CCDC 40 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.”