Ciliary Dyskinesia, Primary, 23

A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-23 (CILD23) is caused by homozygous or compound heterozygous mutation in the ARMC4 gene (615408) on chromosome 10p12.

Description

Primary ciliary dyskinesia-23 is an autosomal recessive disorder resulting from defective ciliary motility. Affected individuals have respiratory distress and recurrent upper and lower airway infections, and they often develop bronchiectasis. About 50% of patients have situs inversus or laterality defects. Ultrastructural analysis of respiratory cilia shows defects in the outer dynein arm (summary by Hjeij et al., 2013).

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

Clinical Features

Hjeij et al. (2013) reported 12 patients from 10 families with CILD. All affected individuals had recurrent upper and lower airway disease as well as bronchiectasis. Seven of 12 individuals had neonatal respiratory distress syndrome. In addition, 8 of the 12 affected individuals had situs inversus totalis and 4 had situs solitus. All tested individuals had low levels of nasal nitric oxide.

Inheritance

The transmission pattern of CILD23 in the families reported by Hjeij et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 12 patients from 10 families with CILD23, Hjeij et al. (2013) identified homozygous or compound heterozygous mutations in the ARMC4 gene (see, e.g., 615408.0001-615408.0004). The first mutation, which was a deletion, was found by copy number variation analysis of candidate genes from the ciliary proteome, and the subsequent mutations were found by targeted sequencing of 135 CILD patients with outer dynein arm defects. Overall, there was 1 deletion, 6 mutations resulting in premature stop codons, and 1 missense mutation. Respiratory cells from patients with truncating mutations showed absence of ARMC4 localization in the ciliary axonemes, and video microscopy showed either markedly reduced ciliary beat frequency and amplitude or complete immotility, consistent with severe outer dynein arm defects. Transmission electron microscopy of these cilia showed a marked reduction of outer dynein arms, but not a complete loss of axonemal outer dynein arm assembly. Immunofluorescence studies showed absence of DNAH5 (603335) and DNAI2 (605483) from the distal ciliary axonemes, indicating partial defects of the outer dynein arms. In these studies, cilia from patients with the missense mutation (L927W; 615408.0002) showed less severe anomalies, consistent with partial retention of protein function.

In 5 patients from 2 unrelated consanguineous families of Turkish and Pakistani origin, respectively, with CILD23, Onoufriadis et al. (2014) identified 2 different homozygous truncating mutations in the ARMC4 gene (615408.0004 and 615408.0005). The mutations were found by whole-exome or whole-genome sequencing. Electron microscopy of patient nasal epithelial cells showed a loss of the distal outer dynein arms, and video microscopy showed that the cilia were immotile. Immunofluorescence studies showed reduced levels of ARMC4 along the cilia axoneme compared to controls, with abnormal accumulation of ARMC4 in the cell body.

Animal Model

Hjeij et al. (2013) found that morpholino-mediated knockdown of zebrafish armc4 resulted in dose-dependent defects in heart looping. Expression of wildtype human ARMC4 caused significant rescue of abnormal unlooped or rightward looping phenotypes. Hjeij et al. (2013) also identified a recessive missense mutation, met993 to lys, in the Armc4 gene in the Aotea mouse line, which was generated in an N-ethyl-N-nitrosourea mutation screen. Among homozygous Aotea mutants with abnormal laterality, half had situs inversus and half exhibited heterotaxy, indicating randomized laterality. Aotea mutants had a range of cardiovascular anomalies, including right aortic arch, perimembranous and muscular ventricular septal defects, ventricular noncompaction, and anomalous venous return. Homozygous mutants developed hydrocephalus at 3 to 4 weeks of age and succumbed prior to reproductive age. Respiratory cilia of Aotea mutants were either immotile or had slow dyskinetic motion compared with wildtype cilia. Transmission electron microscopy of tracheal airway cilia revealed a reduction in outer dynein arms, consistent with a defect in outer dynein arm assembly.