Ciliary Dyskinesia, Primary, 28

A number sign (#) is used with this entry because primary ciliary dyskinesia-28 (CILD28) is caused by homozygous or compound heterozygous mutation in the SPAG1 gene (603395) on chromosome 8q22.

Description

Primary ciliary dyskinesia-28 is an autosomal recessive disorder caused by defective ciliary movement. Affected individuals have recurrent upper and lower airway disease, bronchiectasis, and decreased fertility. About half of patients show laterality defects, including situs inversus. Respiratory cilia from patients show defects in both the inner and outer dynein arms (summary by Knowles et al., 2013).

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

Clinical Features

Knowles et al. (2013) reported 14 patients from 11 unrelated families with primary ciliary dyskinesia. All patients had classic features of CILD with or without situs inversus, including neonatal respiratory distress, recurrent sinopulmonary infections, and decreased nasal nitric oxide. Analysis of patient cilia showed combined defects of the inner and outer dynein arms and nearly complete ciliary immotility.

Molecular Genetics

In 3 sibs with primary ciliary dyskinesia with inner and outer dynein arm defects, Knowles et al. (2013) identified compound heterozygosity for a mutation in the SPAG1 gene (603395.0001) and a large 11.97-kb deletion involving the SPAG1 gene (603395.0002). The initial mutation was found by whole-exome sequencing of the proband, and the genetic defects segregated with the disorder in the family. Further analysis of the SPAG1 gene using a combination of methods in 98 individuals with various forms of CILD identified biallelic pathogenic mutations in the SPAG1 gene (see, e.g., 603395.0003-603395.0005) in 11 additional patients from 10 unrelated families. Patient cilia showed absent staining for the outer dynein chain DNAH5 (603335) and the inner light chain DNALI1 (602135). In addition, these mutant cilia were defective in both the proximal and distal types of outer dynein arms. These findings suggested that SPAG1 is involved in the preassembly of axonemal components.

Animal Model

Knowles et al. (2013) found that morpholino knockdown of the Spag1 ortholog in zebrafish resulted in defects consistent with a ciliopathy, including dorsal body axis curvature and hydrocephalus.