Ciliary Dyskinesia, Primary, 30

A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-30 (CILD30) is caused by homozygous mutation in the CCDC151 gene (615956) on chromosome 19p13.

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

Clinical Features

Hjeij et al. (2014) reported 5 patients from 3 unrelated families with primary ciliary dyskinesia. All had recurrent upper and lower airway disease with chronic respiratory symptoms and bronchiectasis, as well as nasal blockages, polyps, and otitis media. Four of the 5 patients had very early involvement, with neonatal respiratory distress. Four patients had laterality defects, including dextrocardia and/or abdominal situs inversus.

Alsaadi et al. (2014) reported a boy, born of consanguineous parents of Arab descent, with primary ciliary dyskinesia. Clinical features included bronchiectasis, bronchial asthma, recurrent chest infections, low nasal nitric oxide levels, and a long history of wet cough. He also had allergic rhinitis and pectus excavatum. Electron microscopic analysis of patient cilia showed that the axonemes did not assemble a full complement of inner and outer dynein arms, with absence of inner and outer dynein arms. The cilia were immotile in the tissue analyzed.

Inheritance

The transmission pattern of CILD30 in the families reported by Hjeij et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 3 unrelated families with CILD30, Hjeij et al. (2014) identified 2 different homozygous truncating mutations in the CCDC151 gene (E309X, 615956.0001; S419X, 615956.0002). The mutations were found by combined high-throughput mapping and sequencing as well as by linkage analysis in 1 consanguineous family. These families were ascertained from more than 280 CILD individuals studied, suggesting that CCDC151 mutations are a rare cause of the disorder. Patient respiratory epithelial cells showed loss of the CCDC151 protein and had completely immotile cilia compared to controls, consistent with a loss of function. Respiratory cilia axonemes showed lack of DNAH5 (603335), indicating a loss of the outer dynein arms, but normal expression and localization of DNALI1 (602135), indicating that the inner dynein arm assembly is unaffected.

In a boy, born of consanguineous Arab parents, with CILD30, Alsaadi et al. (2014) identified homozygosity for the E309X mutation in the CCDC151 gene. The mutation was found by whole-exome sequencing and segregated with the disorder in the family.

Animal Model

Hjeij et al. (2014) determined that the mutant mouse 'Snowball' (Snbl) results from a homozygous splice site mutation (c.828+2A-G) in exon 6 of the Ccdc151 gene that results in a complete loss of function. Snbl mice had a spectrum of laterality defects, including complex congenital heart defects associated with heterotaxy, and airway epithelia from the mutant mice showed largely immotile cilia with loss of the outer dynein arms.

Jerber et al. (2014) found that morpholino-mediated knockdown of ccdc151 in zebrafish embryos resulted in defects in left-right symmetry, dilated pronephros, small kidney cysts, and hydrocephalus. Imaging revealed defective beating of cilia in Kupfer vesicles. Ccdc151 morphants showed defects in the number of axonemal dynein (see 600112) arms as well as loss of ciliary localization of ccdc114 (615038) in pronephric cilia. Morphants also showed mislocalization of basal bodies in floor plate cells and altered orientation of cell division in pronephros.

Hjeij et al. (2014) determined that the zebrafish 'flanders' mutant, which has a ventral curved body and kidney cysts consistent with abnormal ciliary motility, results from a c.631T-A transversion in exon 6 of the ccdc151 gene, resulting in a lys211-to-ter (K211X) substitution and nonsense-mediated mRNA decay with a complete loss of protein expression. Mutant embryos showed randomization of situs inversus and abnormally irregular or static ciliary movement; ultrastructural analysis showed loss of the outer dynein arms. The phenotype could be rescued by injection of wildtype ccdc151 mRNA. In situ hybridization studies of normal zebrafish found expression of the ccdc151 gene in tissues that contain motile cilia. Knockdown of ccdc151 in flatworm planarians resulted in severely reduced locomotive ability due to ciliary defects.