A novel hypomorphic allele ofSpag17causes primary ciliary dyskinesia phenotypes in mice

Abstract

Primary ciliary dyskinesia (PCD) is a human condition of dysfunctional motile cilia characterized by recurrent lung infection, infertility, organ laterality defects, and partially penetrant hydrocephalus. We recovered a mouse mutant from a forward genetic screen that developed all the phenotypes of PCD. Whole exome sequencing identified this primary ciliary dyskinesia only (Pcdo) allele to be a nonsense mutation (c.5236A>T) in the Spag17 coding sequence creating a premature stop codon at position 1746 (K1746*). The Pcdo variant abolished different isoforms of SPAG17 in the Pcdo mutant testis but not in the brain. Our data indicate differential requirements for SPAG17 in different motile cilia cell types. SPAG17 is required for proper development of the sperm flagellum, and is essential for either development or stability of the C1 microtubule structure within cilia, but not the brain ependymal cilia. We identified changes in ependymal cilia beating frequency but these did not apparently alter lateral ventricle cerebrospinal fluid (CSF) flow. Aqueductal (Aq) stenosis resulted in significantly slower and abnormally directed CSF flow and we suggest this is the root cause of the hydrocephalus. The Spag17Pcdo homozygous mutant mice are generally viable to adulthood, but have a significantly shortened life span with chronic morbidity. Our data indicate that the c.5236A>T Pcdo variant is a hypomorphic allele of Spag17 gene that causes phenotypes related to motile, but not primary, cilia. Spag17Pcdo is a novel and useful model for elucidating the molecular mechanisms underlying development of PCD in the mouse.

Central Apparatus, the Molecular Kickstarter of Ciliary and Flagellar Nanomachines

“…The respiratory CFs beat with altered waveform and sometimes frequency and showed some ultrastructural defects. Moreover, in mutant testes, the mature sperm cells were not formed, suggesting that the truncated Spag17 was not sufficient for spermatogenesis [ 106 ]. In contrast, sub-C-terminally located point mutation of SPAG17 in a human patient caused asthenozoospermia -related infertility, but not PCD [ 76 ].…”

Ccdc103 promotes myeloid cell proliferation and migration independent of motile cilia

“…Presently, mutations in more than 40 different gene products have been implicated in PCD ( Horani et al, 2016 ). The genes most commonly mutated in this disorder include those coding for light-, intermediate- and heavy-chain subunits of axonemal dynein and their associated chaperones/assembly factors required for ciliary motility, including dynein axonemal assembly factor 1 (DNAAF1), and microtubule-binding proteins such as sperm-associated antigen 1 (SPAG1) and SPAG17 ( Knowles et al, 2013 ; Tarkar et al, 2013 ; Horani et al, 2016 ; Abdelhamed et al, 2020 ). One of these axonemal dynein assembly factors is coiled-coil domain-containing protein 103 (CCDC103).…”