DYX1C1 is required for axonemal dynein assembly and ciliary motility

Abstract

SUMMARY Dyx1c1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deletion of Dyx1c1 exons 2–4 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a genetically heterogeneous disorder characterized by chronic airway disease, laterality defects, and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1c.T2A start codon mutation recovered from an ENU mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also created laterality and ciliary motility defects. In humans, recessive loss-of-function DYX1C1 mutations were identified in twelve PCD individuals. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans revealed disruptions of outer and inner dynein arms (ODA/IDA). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA/IDA assembly factor DNAAF2/KTU. Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4).

Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population

“…Although no single-nucleotide variants or indels were identified in either gene, copy-number variant/exon deletion analysis identified a homozygous deletion of B3.5 kb in DYX1C1, which has been previously reported in a family with PCD (Figure 3c). 12 The deletion was confirmed by SNP genotyping and PCR (Supplementary Figure S1; Supplementary Table S1). SNP genotyping showed that the deletion was not present in 200 control chromosomes from the Irish and Irish Traveller populations.…”

“…In some cases Severe defects in IDA and ODA Immotile cilia or cilia with a reduced beat frequency and amplitude German, 12 Belgian, 12 Austrian, 12 American, 12 Consanguineous Irish, 12 Irish Traveller a DNAH11…”

Antagonistic interactions in the zebrafish midline prior to the emergence of asymmetric gene expression are important for left–right patterning

“…In vertebrates, a major model for how L-R asymmetries are initiated involves an asymmetric fluid flow within LRCs, driven by the rotation of polarized motile cilia [19,20,23,[45][46][47][48][49][50][51][52][53]. In support of this model, a plethora of mutants that exhibit cilia motility abnormalities also display defects of L-R patterning (for just a few examples see [54][55][56][57][58] Once asymmetric gene expression is established in the LPM, midline structures are also critical for maintaining asymmetries. Initial analysis of zebrafish mutants, in which an intact notochord fails to form, revealed defects in asymmetric gene expression in the LPM with subsequent abnormalities in cardiac asymmetry [76][77][78].…”

Insights into the Genetic Foundations of Human Communication

“…Research examining the basic biology of these proteins has led to some interesting discoveries. For example, DYX1C1 has been shown to play a role in the primary cilium and mutations of this gene are now known to cause a monogenic form of the disorder primary ciliary dyskinesis (Carrion-Castillo et al 2013;Tarkar et al 2013). In utero gene knockdown in rats has been a major strategy for examining the role of dyslexia candidate genes in brain development (Szalkowski et al 2012;Threlkeld et al 2007;Gabel et al 2011).…”