NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a hereditary defect of motile cilia in humans and several domestic animal species. Typical clinical findings are chronic recurrent infections of the respiratory tract and fertility problems. We analyzed an Alaskan Malamute family, in which two out of six puppies were affected by PCD. The parents were unaffected suggesting autosomal recessive inheritance. Linkage and homozygosity mapping defined critical intervals comprising ~118 Mb. Whole genome sequencing of one 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. Nme5-/- knockout mice exhibit doming of the skull, hydrocephalus and sperm flagellar defects. 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. The mutant allele was not present in more than 1000 control dogs from different breeds. Immunohistochemistry demonstrated absence of the NME5 protein from nasal epithelia of an affected dog. We therefore propose NME5:c.43delA as the most likely candidate causative variant for PCD in Alaskan Malamutes. These findings enable genetic testing to avoid the unintentional breeding of affected dogs in the future. Furthermore, the results of this study identify NME5 as a novel candidate gene for unsolved human PCD and/or hydrocephalus cases.

AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease

“…Intersecting the linked and homozygous regions delineated critical intervals comprising 19 segments on 10 chromosomes spanning 99 Mb or roughly 4.1% of the 2.4 Gb dog genome. The two known canine PCD causative variants, CCDC39 :c.286C>T [5] and NME5 :c.43delA [6] were not located in the critical intervals and could thus be excluded.…”

“…PCD causative genetic variants were also reported in purebred dogs. Variants in CCDC39 [5] and NME5 [6] were identified in PCD affected Old English Sheepdogs and Alaskan Malamutes, respectively. Despite the extensive knowledge about PCD, there are also clinically described forms of inherited recurrent inflammatory airway disease in humans and dogs, whose underlying genetic cause is still unknown [7,8].…”

Recessive missense LAMP3 variant associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs

“…Dogs have become excellent natural models for human disease as inherited disorders have been enriched in many dog breeds due to strict selective breeding schemes and breed structures [10,11]. With the rapid advancement of gene technologies, studies in dogs have unraveled novel disease genes and mechanisms [12][13][14][15][16]. These discoveries can advance the understanding of the corresponding human diseases, while animals and breeding programs will benefit from genetic testing.…”

Rsph4a is essential for the triplet radial spoke head assembly of the mouse motile cilia

“…We finally examined the localization of Rsph23, a homolog of Chlamydomonas neck/arch protein Rsp23 [20,25,[31][32][33][34]. A very recent work reports that Mutation of Rsph23/NME5 leads to PCD phenotype in Alaskan Malamutes [34]. In the WT mice, ciliary localization of Rsph23 was observed in the trachea, ependymal, and oviduct cells ( Fig 5S-5U, Fig 6S-6U, Fig 7S-7U).…”

“…The immunofluorescence data and the western blotting data suggest that Rsph4a is essential for the assembly of the spoke head complex in the mouse motile cilia. We finally examined the localization of Rsph23, a homolog of Chlamydomonas neck/arch protein Rsp23 [20,25,[31][32][33][34]. A very recent work reports that Mutation of Rsph23/NME5 leads to PCD phenotype in Alaskan Malamutes [34].…”