Ciliary Dyskinesia, Primary, 27

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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 primary ciliary dyskinesia-27 (CILD27) is caused by homozygous mutation in the CCDC65 gene (611088) on chromosome 12q13.

Description

Primary ciliary dyskinesia-27 is an autosomal recessive disorder caused by defective ciliary movement. Affected individuals have neonatal respiratory distress, recurrent upper and lower airway disease, and bronchiectasis. Respiratory cilia from patients show defects in the inner dynein arms and nexin links. Situs inversus has not been reported in these patients (summary by Austin-Tse et al., 2013).

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

Clinical Features

Austin-Tse et al. (2013) reported 2 brothers and an unrelated girl, all of Ashkenazi Jewish descent, with primary ciliary dyskinesia. The patients had recurrent bronchitis, sinusitis, and/or otitis media, but no situs inversus. Fertility status could not be ascertained. Cilia ultrastructure showed normal outer dynein arms, radial spokes, and central pairs, but there was a reduction in inner dynein arms and nexin links. Microtubule disorganization was also observed in 5 to 15% of cilia cross-sections, suggesting that the reduction in nexin links may lead to overall structural instability in a subset of cilia. Live imaging of patient nasal epithelial cilia showed a stiff, dyskinetic cilia waveform.

Horani et al. (2013) reported an 18-year-old boy of Ashkenazi Jewish descent with primary ciliary dyskinesia without laterality defects. He presented in early infancy with recurrent respiratory infections resulting in cystic bronchiectasis. Nasal nitric oxide levels were reduced. Nasal respiratory epithelial cells showed normal ciliary axonemal structure on electron microscopy, but the ciliary beat pattern was abnormally stiff and hyperkinetic compared to controls.

Inheritance

The transmission pattern of CILD27 in the families reported by Austin-Tse et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 Ashkenazi Jewish patients, including 2 brothers, with primary ciliary dyskinesia-27, Austin-Tse et al. (2013) identified a homozygous truncating mutation in the CCDC65 gene (611088.0001). The patients were ascertained from a larger cohort of 295 individuals with CILD.

Horani et al. (2013) also identified a homozygous truncating mutation in the CCDC65 gene (611088.0001) in a CILD27 patient of Ashkenazi Jewish descent. The patient did not have laterality defects. Immunohistochemical studies of patient nasal epithelial cells showed absence of the CCDC65 protein as well as absence of GAS8 (605178), another member of the nexin-dynein regulatory complex (N-DRC). Similar results were obtained after shRNA knockdown of CCDC65 in control respiratory epithelial cells.

Animal Model

Austin-Tse et al. (2013) found that morpholino knockdown of the CCDC65 gene in zebrafish resulted in a strong ciliopathy phenotype, including pronephric cysts, axis curvature, left-right asymmetry defects, and hydrocephalus. Immunostaining for certain ciliary proteins did not detect structural abnormalities, and ultrastructure analysis showed that the outer dynein arms were not missing. High-speed video microscopy showed paralyzed or dyskinetic cilia, consistent with a motility defect.