Ciliary Dyskinesia, Primary, 21

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

DNAAF3, DRC1, DNAI1, CCDC151, ARMC4, FOXJ1, DNAAF4, CCDC40, RSPH1, CCDC114, DNAH9, ZMYND10, LRRC6, PIH1D3, CCDC65, CFAP300, CFAP221, DNAH1, CCDC103, RSPH3, TTC25, SPEF2, CFAP298, MCIDAS, HYDIN, DNAAF5, RPGR, SPAG1, GAS8, STK36, OFD1, GAS2L2, CCNO, DNAH5, LRRC56, DNAJB13, DNAH11, CCDC39, DNAI2, SLIT2, AP1B1, C1orf127, RSPH9, NME8, PCBD1, DNAAF1, RSPH4A, AK7, CDO1, DNAH6, CFTR, SIT1, TCTE3, MBL2, RFX1, NME7, TXN, TEKT1, DNAL1, NME5, WDR19, DNAH7, CHD7, DPCD, CDON, NTM, ACVR2B

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A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-21 (CILD21) is caused by homozygous mutation in the DRC1 gene (615288) on chromosome 2p23.

Description

Primary ciliary dyskinesia-21 is an autosomal recessive ciliopathy characterized by infantile onset of chronic sinopulmonary infections resulting from abnormal ciliary function. Electron microscopy of respiratory epithelial cells shows normal outer and inner dynein arms, but absence of nexin links and defects in the nexin-dynein regulatory complex (N-DRC). Video microscopy of patient cilia shows an increased beat frequency with decreased bending amplitude (summary by Wirschell et al., 2013).

For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Clinical Features

Carlen et al. (2003) reported 2 Swedish brothers with primary ciliary dyskinesia. Both had repeated upper and lower respiratory tract infections and recurrent otitis media since birth. They also reported an unrelated Swedish woman with similar symptoms, including sinusitis and pulmonary atelectasis. None of the patients had situs inversus. Transmission electron microscopy of nasal brush biopsies showed normal 9+2 ciliary patterns and the outer and inner dynein arms and radial spokes also appeared normal. However, nexin links could not be discerned, and some of the cilia appeared disorganized. Nasal nitric oxide (NO) was consistently low.

Wirschell et al. (2013) reported a 15-year-old Austrian boy of Turkish ancestry with primary ciliary dyskinesia. The patient had neonatal respiratory distress, recurrent pneumonia since infancy, and chronic suppurative otitis media and chronic sinusitis. CT scan at age 12 years showed showed bronchiectasis, and nasal NO production was decreased, consistent with primary ciliary dyskinesia. Nasal respiratory cilia showed normal outer doublet microtubules, but careful analysis of the cross-sections identified more subtle ultrastructural changes indicative of alterations in the nexin-dynein regulatory complex, which regulates dynein motors. Mutant respiratory cilia lacked nexin links in all the analyzed cross-sections.

Inheritance

The transmission pattern of CILD21 in the families reported by Wirschell et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients, including 2 sibs, with primary ciliary dyskinesia, Wirschell et al. (2013) identified homozygous truncating mutations in the DRC1 gene (615288.0001 and 615288.0002). The first mutation was found using homozygosity mapping combined with candidate gene sequencing. Examination of the mutant respiratory cilia showed normal inner and outer dynein arms, but nexin links were lacking, and there was decreased expression of the DRC proteins GAS8 (605178) and LRRC48, confirming that DRC1 deficiency disrupts assembly of the nexin-dynein regulatory complex. Video microscopy of patient cilia showed an increased beat frequency with decreased bending amplitude.

Animal Model

Wirschell et al. (2013) reported that the Chlamydomonas mutant pf3, which lacks Drc1, has defective assembly of the ciliary nexin-dynein regulatory complex and the calmodulin (see 114180) spoke-associated complex.