Ciliary Dyskinesia, Primary, 3

A number sign (#) is used with this entry because primary ciliary dyskinesia-3 (CILD3) is caused by homozygous or compound heterozygous mutation in the DNAH5 gene (603335) on chromosome 5p15.

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

Description

Primary ciliary dyskinesia is an autosomal recessive disorder resulting from loss of normal ciliary function. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus, and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003).

Clinical Features

Omran et al. (2000) studied a large consanguineous family of Arabic origin with primary ciliary dyskinesia. Direct examination of the respiratory cilia revealed ciliary akinesia, and electron microscopy of cilia showed absence of the outer dynein arms. Two of 4 affected individuals exhibited situs inversus, typical for Kartagener syndrome, due to randomization of the left/right body axis.

Mapping

In an Arabic family, Omran et al. (2000) performed a total genome scan with 340 highly polymorphic microsatellites and localized the locus for Kartagener syndrome to a region of homozygosity by descent on chromosome 5p15-p14, with a maximum parametric multipoint lod score of 3.51, flanked by markers D5S2095 and D5S502 within an interval of 20 cM sex-averaged genetic distance. Applying a PCR-based approach, Omran et al. (2000) identified a 1.5-kb partial cDNA of DNAH5 encoding the Chlamydomonas-related axonemal heavy dynein chain within the critical disease interval of this locus.

Molecular Genetics

Olbrich et al. (2002) found 7 individuals from 6 families with primary ciliary dyskinesia or Kartagener syndrome who had mutations in the DNAH5 gene (see, e.g., 603335.0001-603335.0003). In 5 of these families there were affected individuals with and without situs inversus within the same sibship, indicating randomization of left-right axis asymmetry in individuals carrying DNAH5 mutations.

Failly et al. (2009) identified 18 novel and 6 previously described DNAH5 mutations in 16 (18%) of 89 unrelated individuals with primary ciliary dyskinesia, including 13 (15%) individuals in whom DNAH5 mutations were identified on both alleles. These DNAH5 mutations were mainly associated with outer and inner dyneins arm ultrastructural defects (50%).

In 2 sibs and an unrelated patient with CILD3, Knowles et al. (2013) identified compound heterozygous mutations in the DNAH5 gene (603335.0006-603335.0009). The mutations were identified by exome sequencing. Features included sinusitis, otitis, bronchiectasis, and decreased nasal nitric oxide. Two had situs inversus. Respiratory epithelial cells showed defects in the outer dynein arms of cilia.

Animal Model

Ibanez-Tallon et al. (2002) characterized an insertional mutation in the mouse Dnah5 gene that resulted in recurrent respiratory infections, situs inversus, and ciliary immotility. These mice also suffered from hydrocephalus and died perinatally. Electron microscopic studies demonstrated the loss of axonemal outer arms. Comparison of the mouse model and the human data suggested that the degree of ciliary dysfunction may be causally related to the severity of the human phenotype, particularly the presence of hydrocephalus.

Tan et al. (2007) found that mutant mice with a recessive deletion mutation in the Dnah5 gene had PCD and that 40% of these mice also had heterotaxy. Fetuses with heterotaxy showed varying combinations of complex structural heart defects, including double-outlet right ventricle, superior-inferior ventricles, artery alignment defects, and interrupted vena cava. Visceral situs abnormalities, such as abnormally lobed lungs and liver, were less commonly observed. Some surviving mice showed hydrocephaly. Diagnosis of PCD was confirmed by electron microscopy, which showed missing outer dynein arms in the respiratory cilia. The findings suggested that immotile or dyskinetic cilia are associated with random lateralization during embryonic development, and that mutations in the Dnah5 gene result in both PCD and heterotaxy.