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
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.”
462-472
Anthony, Dinu
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Becker-Heck, Anita
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Zariwala, Maimoona A.
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Schmidts, Miriam
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Onoufriadis, Alexandros
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Forouhan, Mitra
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Wilson, Robert
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Taylor-Cox, Theresa
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Dewar, Ann
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Jackson, Claire
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5 March 2013
Anthony, Dinu
e89f7393-6e90-4681-b9ce-f21fb59e2274
Becker-Heck, Anita
71c2ef4d-ee49-4e83-9d04-90e7f2502664
Zariwala, Maimoona A.
92e7d8eb-8ba3-4156-9af3-ce4f31c9a5ce
Schmidts, Miriam
a99571c8-de4a-44a2-8478-2e463ee67fda
Onoufriadis, Alexandros
2ac49db8-6d17-49ea-ba04-0bf579f28bf1
Forouhan, Mitra
bf3eaacb-0079-4b59-9a43-f69ae0189779
Wilson, Robert
86279e42-af90-4ddd-b5ab-5444a0d69ca9
Taylor-Cox, Theresa
a8c56fd2-1a97-443e-8563-446a529a7256
Dewar, Ann
05874b03-a296-4eef-b19d-82655ddb448f
Jackson, Claire
64cdd6fa-74c3-4ac6-94ef-070620a6efd9
Anthony, Dinu, Becker-Heck, Anita, Zariwala, Maimoona A., Schmidts, Miriam, Onoufriadis, Alexandros, Forouhan, Mitra, Wilson, Robert, Taylor-Cox, Theresa, Dewar, Ann and Jackson, Claire
(2013)
Mutations in CCDC39 and CCDC40 are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms.
Human Mutation, 34 (3), .
(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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Published date: 5 March 2013
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Local EPrints ID: 469975
URI: http://eprints.soton.ac.uk/id/eprint/469975
ISSN: 1059-7794
PURE UUID: d3950a28-a95e-4ebc-9005-8666de71f6d9
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Date deposited: 29 Sep 2022 16:43
Last modified: 17 Mar 2024 03:02
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Author:
Dinu Anthony
Author:
Anita Becker-Heck
Author:
Maimoona A. Zariwala
Author:
Miriam Schmidts
Author:
Alexandros Onoufriadis
Author:
Mitra Forouhan
Author:
Robert Wilson
Author:
Theresa Taylor-Cox
Author:
Ann Dewar
Author:
Claire Jackson
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