Categories: Respiratory system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 603575 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: Motile cilia are required for clearing mucous, infectious agents and inhaled dust from the airways. Primary ciliary dyskinesia (PCD) is a hereditary defect of motile cilia. Clinical findings may include recurrent airway infections, fertility problems, and sometimes hydrocephalus. (Tosso Leeb 10 Sep 2019)

Species-specific description: Several types of primary ciliary dyskinesia exist. See also 'OMIA001540-9615 : Ciliary dyskinesia, primary, CCDC39-related in Canis lupus familiaris' and 'OMIA000573-9615 : Ciliary dyskinesia, primary, generic in Canis lupus familiaris'.

Molecular basis: Anderegg et al. (2019): "Whole genome sequencing of one [Alaskan Malamute] case and comparison to 601 control genomes identified a disease associated frameshift variant, c.43delA, in the NME5 gene encoding a sparsely characterized protein associated with ciliary function. . . . The genotypes at NME5:c.43delA showed the expected co-segregation with the phenotype in the Alaskan Malamute family. An additional unrelated Alaskan Malamute with PCD and hydrocephalus that became available later in the study was also homozygous mutant at the NME5:c.43delA variant". Immunohistochemistry demonstrated absence of the NME5 protein from nasal epithelia of an affected dog.

Clinical features: Anderegg et al. (2019): "severe bronchial lung pattern and bronchiectasis on thoracic radiographs in both dogs . . . Direct rhinoscopy and bronchoscopy revealed hyperemic mucosa, medium to large amount of mucopurulent secretions along the upper and lower airway tracts and moderate to severe turbinate lysis in the nasal cavity in both dogs . . . Bronchoalveolar lavage fluid was compatible with chronic active purulent bronchopneumonia."

Pathology: Electron microscopy of cilia from nasal epithelium revelaed alterations at the inner and outer dynein arms of motile cilia. Inner dynein arms were shortened or absent in 95% - 100% of the investigated cilia, outer dynein arms were shortend or absent in 60% - 80% of cilia. In normal cilia, there is a 9 + 2 arrangement of microtubules with two single microtubules in the center and nine pairs of peripheral microtubules. In an affected dog, extra peripheral microtubule singlets appeared occasionally (Anderegg et al. 2019).

Prevalence: Anderegg et al. (2019): "The mutant allele was not present in more than 1000 control dogs from different breeds."

Breed: Alaskan Malamute (Dog) (VBO_0200017).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: