期刊
HUMAN MUTATION
卷 34, 期 3, 页码 462-472出版社
WILEY
DOI: 10.1002/humu.22261
关键词
primary ciliary dyskinesia; cilia; CCDC39; CCDC40; radial spoke; dynein regulatory complex; nexin link
资金
- British Heart Foundation [RG/10/13/28570] Funding Source: Medline
- Medical Research Council [MR/K000608/1] Funding Source: Medline
- NCATS NIH HHS [UL1 TR000154, UL1 TR001082, UL1 TR000083] Funding Source: Medline
- NCRR NIH HHS [M01 RR000046] Funding Source: Medline
- NHLBI NIH HHS [T32 HL007106, U54 HL096458, 5 R01HL071798, 5 U54 HL096458-06, R01 HL071798] Funding Source: Medline
- PHS HHS [ULITR000083] Funding Source: Medline
- Wellcome Trust [091551, WT091310, 090532] Funding Source: Medline
- Department of Health [NF-SI-0510-10268] Funding Source: Medline
- Action Medical Research [1773] Funding Source: researchfish
- British Heart Foundation [RG/10/13/28570] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1299] Funding Source: researchfish
- Medical Research Council [MR/K000608/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268] Funding Source: researchfish
- MRC [MR/K000608/1] Funding Source: UKRI
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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