X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

Abstract

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins.

ZMYND10 functions in a chaperone relay during axonemal dynein assembly

“…Our systematic protein-interaction studies are the first to begin mapping mammalian DNAAF functions under physiological conditions. Protein interaction studies and/or homology modeling for DNAAF2, DNAAF4, DNAAF6 and SPAG1 7,8,25,26 place these assembly factors within a cilial-specific configuration of the HSP90 co-chaperone R2TP complex. DNAAF1, LRRC6 and C21ORF59 putatively function in another separate reported complex (Jaffe et al, 2016).…”

Control of assembly of extra-axonemal structures: the paraflagellar rod of trypanosomes

“…This process has a cytoplasmic step during which the dynein arm proteins are folded and assembled into a complex before undergoing further maturation and delivery to the flagellum (Desai et al, 2018). This cytoplasmic step requires an expanding list of dynein arm assembly factors (currently 11 – DNAAF1/LRRC50, DNAAF2/Kintoun, DNAAF3, MOT48, HEATR2, LRRC6, DYX1C1/DNAAF4, PIH1D3/Twister, SPAG1, ZMYND10 (Cho et al, 2018; Desai et al, 2018; Horani et al, 2012; Loges et al, 2009; Mitchison et al, 2012; Mitchison et al, 2012; Olcese et al, 2017; Omran et al, 2008; Tarkar et al, 2013)) that act as chaperones to ensure successful folding and assembly of the dynein arm complex. In the PFR-AF1 null mutant PFR1 and PFR2 protein amount increased when the cells were treated with the proteasome inhibitor MG132, suggesting that without PFR-AF1 PFR1/PFR2 were unstable and degraded.…”

Mutations in C11ORF70 cause primary ciliary dyskinesia with randomization of left/right body asymmetry due to outer and inner dynein arm defects

“…Using C11ORF70 as bait we tested putative interactions with other known preassembly factors, ODA and IDA components, ODA-DC proteins, proteins assumed to be involved in dynein arm transport (WDR69, IFT46) and others (Table S2). Direct interaction between C11ORF70 and possible interactors was tested as previously described (50) .…”

“…Although the process of cytoplasmic pre-assembly of dynein arms is still poorly understood, several genes encoding proteins involved in this process were identified: DNAAF1 (LRRC50, MIM 613190) (39,40) , DNAAF2 (KTU, MIM 612517) (41) , DNAAF3 (C19orf51, MIM 614566) (42) , DNAAF4 (DYX1C1, MIM 608709) (43) , DNAAF5 (HEATR2, MIM 614864) (44) , LRRC6 (MIM 614930) (45) , ZMYND10 (MIM 607070) (46,47) , SPAG1 (MIM 603395) (48) and C21ORF59 (MIM 615494) (49) . Three X-linked PCD variants have been reported so far, one caused by mutations in PIH1D3 (MIM 300933) (50,51) resulting in absence of ODA and IDA and two PCD variants associated with syndromic cognitive dysfunction or retinal degeneration caused by mutations in OFD1 (MIM 311200) and RPGR (MIM 312610), respectively (52,53) . Here, we describe a new ODA/IDA defect caused by recessive loss-of-function mutations in the open reading frame of C11ORF70.…”