The University of Southampton
University of Southampton Institutional Repository

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

Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganisation and absent inner dynein arms
Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganisation 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 disorganisation 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 nexin-dynein regulatory complex (N-DRC) defect', rather than 'radial spoke defect'.
1059-7794
462-472
Antony, Dinu
c910c932-53ae-4d8d-910c-335cad7eae89
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
53052338-4141-4934-a783-7823035738a5
Goggin, Patricia
90c80d17-9f7a-4401-8e6f-919c63efe5e6
Loges, Niki T.
6c4a7ea9-1f6a-407e-a13e-6de7cdc8a5e2
Olbrich, Heike
afa68429-7f05-4e48-b44a-ea7f41a4f4b2
Jaspers, Martine
ce59ac4c-2fc2-4504-981b-bc361e3a2e0c
Jorissen, Mark
55543c06-8e8e-4db9-a5fc-205cb2cd5613
Leigh, Margaret W.
70d7e4e3-28ad-4bd2-a5c1-5daba603e1cb
Wolf, Whitney E.
73e4ca17-f405-451c-a544-c9117160bc6a
Daniels, M. Leigh Anne
5eb83769-e5d3-4c21-bda2-db5b6661e5ad
Noone, Peader G.
ac56147e-491b-4d68-a639-fa11540ae814
Ferkol, Thomas W.
a6efaf0d-e679-40b2-8b1b-bd25445f342c
Sagel, Scott D.
3d899c89-68d0-4859-999e-93e78a4371d8
Rosenfeld, Margaret
ace2f48d-099d-49b8-b0d5-a8949289b767
Rutman, Andrew
b06264ba-bff8-4e7b-b3af-868cfe6369e6
Dixit, Abhijit
0af69ce9-28b7-4bdc-bc43-b48095f4a189
O'Callaghan, Christopher
b985540d-eac0-4308-95d3-ffe156867d45
Lucas, Jane S.
5cb3546c-87b2-4e59-af48-402076e25313
Hogg, Claire
78881fd2-dbe9-4c28-b050-3387c163df1e
Scambler, Peter J.
ccdff85b-5c19-4705-94ce-7167c15fda03
Emes, Richard D.
5962422a-ac02-4807-ab39-951fcb0852ec
Chung, Eddie Mk
7cf5496c-cca0-4651-95d6-8e1ea25b5569
Shoemark, Amelia
6197d7b4-f36b-47bf-b138-373e1aa4b63b
Knowles, Michael R.
164069d2-1ec2-41ce-8bf8-b48462a5a206
Omran, Heymut
49c453b0-2ce2-4925-b5d4-7beffe2bae8d
Mitchison, Hannah M.
3e88e1ba-29d9-4243-8531-d13e66fa1e01
Antony, Dinu
c910c932-53ae-4d8d-910c-335cad7eae89
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
53052338-4141-4934-a783-7823035738a5
Goggin, Patricia
90c80d17-9f7a-4401-8e6f-919c63efe5e6
Loges, Niki T.
6c4a7ea9-1f6a-407e-a13e-6de7cdc8a5e2
Olbrich, Heike
afa68429-7f05-4e48-b44a-ea7f41a4f4b2
Jaspers, Martine
ce59ac4c-2fc2-4504-981b-bc361e3a2e0c
Jorissen, Mark
55543c06-8e8e-4db9-a5fc-205cb2cd5613
Leigh, Margaret W.
70d7e4e3-28ad-4bd2-a5c1-5daba603e1cb
Wolf, Whitney E.
73e4ca17-f405-451c-a544-c9117160bc6a
Daniels, M. Leigh Anne
5eb83769-e5d3-4c21-bda2-db5b6661e5ad
Noone, Peader G.
ac56147e-491b-4d68-a639-fa11540ae814
Ferkol, Thomas W.
a6efaf0d-e679-40b2-8b1b-bd25445f342c
Sagel, Scott D.
3d899c89-68d0-4859-999e-93e78a4371d8
Rosenfeld, Margaret
ace2f48d-099d-49b8-b0d5-a8949289b767
Rutman, Andrew
b06264ba-bff8-4e7b-b3af-868cfe6369e6
Dixit, Abhijit
0af69ce9-28b7-4bdc-bc43-b48095f4a189
O'Callaghan, Christopher
b985540d-eac0-4308-95d3-ffe156867d45
Lucas, Jane S.
5cb3546c-87b2-4e59-af48-402076e25313
Hogg, Claire
78881fd2-dbe9-4c28-b050-3387c163df1e
Scambler, Peter J.
ccdff85b-5c19-4705-94ce-7167c15fda03
Emes, Richard D.
5962422a-ac02-4807-ab39-951fcb0852ec
Chung, Eddie Mk
7cf5496c-cca0-4651-95d6-8e1ea25b5569
Shoemark, Amelia
6197d7b4-f36b-47bf-b138-373e1aa4b63b
Knowles, Michael R.
164069d2-1ec2-41ce-8bf8-b48462a5a206
Omran, Heymut
49c453b0-2ce2-4925-b5d4-7beffe2bae8d
Mitchison, Hannah M.
3e88e1ba-29d9-4243-8531-d13e66fa1e01

Antony, Dinu, Becker-Heck, Anita, Zariwala, Maimoona A., Schmidts, Miriam, Onoufriadis, Alexandros, Forouhan, Mitra, Wilson, Robert, Taylor-Cox, 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, Peader 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 Mk, Shoemark, Amelia, Knowles, Michael R., Omran, Heymut and Mitchison, Hannah M. (2012) Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganisation and absent inner dynein arms. Human Mutation, 34 (3), 462-472. (doi:10.1002/humu.22261). (PMID:23255504)

Record type: Article

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 disorganisation 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 nexin-dynein regulatory complex (N-DRC) defect', rather than 'radial spoke defect'.

Full text not available from this repository.

More information

Published date: 15 December 2012
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 347048
URI: https://eprints.soton.ac.uk/id/eprint/347048
ISSN: 1059-7794
PURE UUID: 41a746cb-50b0-46dd-b541-8dd34d0958a7

Catalogue record

Date deposited: 17 Jan 2013 15:05
Last modified: 16 Jul 2019 21:46

Export record

Altmetrics

Contributors

Author: Dinu Antony
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
Author: Patricia Goggin
Author: Niki T. Loges
Author: Heike Olbrich
Author: Martine Jaspers
Author: Mark Jorissen
Author: Margaret W. Leigh
Author: Whitney E. Wolf
Author: M. Leigh Anne Daniels
Author: Peader G. Noone
Author: Thomas W. Ferkol
Author: Scott D. Sagel
Author: Margaret Rosenfeld
Author: Andrew Rutman
Author: Abhijit Dixit
Author: Christopher O'Callaghan
Author: Jane S. Lucas
Author: Claire Hogg
Author: Peter J. Scambler
Author: Richard D. Emes
Author: Eddie Mk Chung
Author: Amelia Shoemark
Author: Michael R. Knowles
Author: Heymut Omran
Author: Hannah M. Mitchison

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×