Ciliary Dyskinesia, Primary, 26

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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-26 (CILD26) is caused by homozygous or compound heterozygous mutation in the C21ORF59 gene (615494) on chromosome 21q22.

Description

Primary ciliary dyskinesia-26 is an autosomal recessive disorder caused by defective ciliary movement. Affected individuals have neonatal respiratory distress, recurrent upper and lower airway disease, and bronchiectasis. About half of patients show laterality defects, including situs inversus totalis. Respiratory cilia from patients show defects in the inner and outer dynein arms (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 4 unrelated patients with primary ciliary dyskinesia. Two of the patients were of Ashkenazi Jewish descent. Clinical features included neonatal respiratory distress, recurrent respiratory infections, and bronchiectasis. Three patients had situs inversus. All had decreased nasal nitric oxide. Ultrastructural analysis of cilia from affected individuals showed an absence of both outer and inner dynein arm components, and video microscopy of patient respiratory epithelial cell cilia showed complete paralysis.

Inheritance

The transmission pattern of CILD26 in the families reported by Austin-Tse et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 unrelated patients with primary ciliary dyskinesia-26 with or without situs inversus, Austin-Tse et al. (2013) identified 3 different truncating mutations in the C21ORF59 gene (615494.0001-615494.0003). The mutations occurred in homozygous or compound heterozygous state. Two patients of Ashkenazi Jewish descent and 1 of Brazilian descent shared the same truncating mutation (Y245X; 615494.0001); haplotype analysis indicated a founder effect common to all 3 patients. Expression of 1 of the truncating mutations in zebrafish C21orf59 mutants showed that the mutant protein was unstable and failed to rescue the phenotype, consistent with a loss of function. The patients were ascertained from a large cohort of 295 individuals with primary ciliary dyskinesia.

Animal Model

Austin-Tse et al. (2013) found that morpholino knockdown of the C21orf59 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, but ultrastructure analysis revealed that the outer dynein arms were missing. High-speed video microscopy showed paralyzed or dyskinetic cilia, consistent with a motility defect.