Ciliary Dyskinesia, Primary, 39

A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-39, with or without situs inversus (CILD39), is caused by homozygous or compound heterozygous mutation in the LRRC56 gene (618227) on chromosome 11p15.

Description

Primary ciliary dyskinesia-39 (CILD39) is an autosomal recessive disorder characterized by chronic sinopulmonary infections beginning soon after birth and laterality defects in about 50% of patients. Although patient nasal ciliary samples have normal structure, detailed studies may show ciliary kinetic defects in some patients (summary by Bonnefoy et al., 2018).

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

Clinical Features

Bonnefoy et al. (2018) reported 4 patients from 3 unrelated families with a similar disorder suggestive of a ciliopathy. The only affected child in the first family, a girl born of consanguineous Pakistani parents, had recurrent respiratory infections, chronic cough, and ear infections since early infancy. Chest imaging showed dextrocardia and bronchiectasis. Nasal biopsy samples showed intact dynein arms, normal structure, a normal ciliary beat frequency, and particulate clearance. Although cultured epithelial cells at an air-liquid interface produced a healthy ciliated epithelium, the ciliary beat pattern was dyskinetic and the beat frequency was decreased compared to normal. In the second family, 2 male fetuses born of consanguineous Kuwaiti parents were noted to have lethal congenital cardiac malformations on prenatal ultrasound. Both pregnancies were terminated, and postmortem investigation showed similar findings in both individuals, including situs inversus of the thoracic and abdominal organs and complex congenital heart malformations, such as double outlet right ventricle, dominant right ventricle, hypoplastic or absent left ventricle, pulmonic hypoplasia, and atrial situs with atrioventricular discordance. The only patient from family 3 was a 27-year-old man who had situs inversus and neonatal respiratory disease. He had recurrent lower respiratory tract infections with chronic cough and recurrent middle ear disease during childhood and adulthood. Several nasal ciliary biopsies showed normal ciliary structure and normal ciliary beat pattern and frequency with good particulate clearance. Electron microscopy showed normal dynein arms, microtubules, and ciliary length. Bonnefoy et al. (2018) noted that the findings in the 2 patients from the first and third families were not consistent with a formal diagnosis of primary ciliary dyskinesia, but the phenotype was reminiscent of the disorder.

Inheritance

The transmission pattern of CILD39 in the families reported by Bonnefoy et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 3 unrelated families, including 2 male fetuses from 1 family, with CILD39, Bonnefoy et al. (2018) identified homozygous or compound heterozygous mutations in the LRRC56 gene (618227.0001-618227.0004). The mutations, which were found by whole-exome sequencing or next-generation sequencing of a panel of genes, segregated with the disorder in the families. There were 2 splice site mutations, 1 nonsense mutation, and 1 missense mutation. Expression of the corresponding missense mutation (L140P) in T. brucei showed that it caused reduced flagellar motility and a reduction in the number of outer dynein arms, consistent with a partial loss of function. The splice site and nonsense mutations were predicted to result in nonfunctional proteins and a loss of function. Cultured nasal epithelial ciliary cells from 1 of the patients showed a dyskinetic ciliary beat, but no structural ciliary defects, suggesting species variability in LRRC56 function. The findings suggested that LRRC56 acts as a cargo protein and that mutation in this gene causes a defect in dynein transport, rather than ciliary composition or assembly.

Animal Model

Bonnefoy et al. (2018) generated Lrrc56-null T. brucei and observed a significant reduction in flagellar beating and cell swimming, with some cells struggling to complete cell division and remaining attached by their posterior extremities. The phenotypes suggested slow cytokinesis and increased generation times, typical of motility defects in T. brucei. Microscopic analysis revealed that motility defects in Lrrc56-null T. brucei were due to the absence of outer dynein arms in the distal portion of the axoneme. Lrrc56-null cells also appeared to have shorter cilia. Mutation of leu259 of Lrrc56 in T. brucei, which corresponds to human leu140, resulted in reduced motility, but not to the same extent as in Lrrc56-null T. brucei. The authors concluded that Lrrc56 with the leu259 mutation could associate with intraflagellar transport (IFT) trains, but that it functioned less efficiently than the wildtype protein in supporting dynein arm assembly.