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PMID:23255504

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Citation

Antony, D, Becker-Heck, A, Zariwala, MA, Schmidts, M, Onoufriadis, A, Forouhan, M, Wilson, R, Taylor-Cox, T, Dewar, A, Jackson, C, Goggin, P, Loges, NT, Olbrich, H, Jaspers, M, Jorissen, M, Leigh, MW, Wolf, WE, Daniels, ML, Noone, PG, Ferkol, TW, Sagel, SD, Rosenfeld, M, Rutman, A, Dixit, A, O'Callaghan, C, Lucas, JS, Hogg, C, Scambler, PJ, Emes, RD, Uk10k, Chung, EM, Shoemark, A, Knowles, MR, Omran, H and Mitchison, HM (2013) Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Hum. Mutat. 34:462-72

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."

Links

PubMed PMC3630464 Online version:10.1002/humu.22261

Keywords

Alleles; Axoneme/genetics; Axoneme/pathology; Cilia/genetics; Cilia/pathology; Cytoskeletal Proteins/genetics; Dyneins/genetics; Exome; Female; Fluorescent Antibody Technique; Humans; Kartagener Syndrome/genetics; Male; Microscopy, Electron; Mutation; Pedigree; Phenotype; Proteins/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CCD40

located_in

GO:0005930: axoneme

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RSH4A

located_in

GO:0005930: axoneme

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CCD39

involved_in

GO:0030317: flagellated sperm motility

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCD39

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCD39

involved_in

GO:0003356: regulation of cilium beat frequency

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCD39

involved_in

GO:0036159: inner dynein arm assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCD40

part_of

GO:0005930: axoneme

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CCD40

involved_in

GO:0036159: inner dynein arm assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCD40

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCD40

involved_in

GO:0003356: regulation of cilium beat frequency

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCD40

involved_in

GO:0030317: flagellated sperm motility

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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