Ciliary Dyneins and Dynein Related Ciliopathies

Abstract

Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.

Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases

“…Dynein assembly factor is important for the assembly of both outer and inner dynein arms. Mutations in central pair and radial spoke genes does not cause laterality defect, adapted from ( Antony et al, 2021 ). Proteins encoded by genes identified in this study are indicated in red.…”

Hedgehog Morphogens Act as Growth Factors Critical to Pre- and Postnatal Cardiac Development and Maturation: How Primary Cilia Mediate Their Signal Transduction

“…The authors observed that the AVSD phenotype only occurred in Dnah11 avc4 mutant embryos suffering from heterotaxy. This phenotype is usually attributed to dysfunctions of the embryonic node, and the authors attribute the AVSD as a downstream consequence of perturbations in laterality determination, a general principle that has been concluded by other researchers [ 69 , 83 , 84 ]. In contrast, in the same screen, the authors identified a mutation in the primary cilium IFT gene Ift172 and also a nonsense mutation in the Mks1 (Meckel syndrome, type 1) gene [ 83 ].…”

“…By contrast, nodal cilia ultrastructure is characterized by the presence of inner and outer axonemal dynein arms that are located in between microtubules doublet pairs. These dynein arms serve to connect one microtubule doublet to the adjacent/preceding microtubule doublet in a manner that results in the bending motion observed in nodal and motile cilia [ 69 ]. This unique ultrastructure allows nodal cilia to move in an active swirling motion to mediate left–right patterning during late gastrulation and prior to the onset of organogenesis [ 48 ].…”

Base editing derived models of human WDR34 and WDR60 disease alleles replicate retrograde IFT and hedgehog signaling defects and suggest disturbed Golgi protein transport

“…B ) Schematic of Dynein-2 motor structure. The two intermediate chains WDR34 and WDR60 bind to the heavy chains as a heterodimeric complex with light chain binding mediated by the N-terminals, adapted from (Antony et al, 2021). C) WDR60 protein structure.…”