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Multiomics analysis of a DNAH5-mutated PCD organoid model revealed the key role of the TGF-β/BMP and Notch pathways in epithelial differentiation and the immune response in DNAH5-mutated patients

ABSTRACT: Dynein axonemal heavy chain 5 (DNAH5) is the most mutated gene in primary ciliary dyskinesia (PCD), leading to abnormal cilia ultrastructure and function. Few studies have revealed the genetic characteristics and pathogenetic mechanisms of PCD caused by DNAH5 mutation. Here, we established a child PCD airway organoid directly from the bronchoscopic biopsy of a patient with DNAH5 mutation. We found abnormal ciliary function and a decreased immune response caused by DNAH5 mutation through single-cell RNA sequencing (scRNA-seq).

ORGANISM(S): Homo sapiens

PROVIDER: GSE217596 | GEO | 2022/11/12

REPOSITORIES: GEO

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Multiomics analysis of a DNAH5-mutated PCD organoid model revealed the key role of the TGF-β/BMP and Notch pathways in epithelial differentiation and the immune response in DNAH5-mutated patients

Project description:Dynein axonemal heavy chain 5 (DNAH5) is the most mutated gene in primary ciliary dyskinesia (PCD), leading to abnormal cilia ultrastructure and function. Few studies have revealed the genetic characteristics and pathogenetic mechanisms of PCD caused by DNAH5 mutation. Here, we established a child PCD airway organoid directly from the bronchoscopic biopsy of a patient with DNAH5 mutation. We found abnormal ciliary function and a decreased immune response caused by DNAH5 mutation through proteomic analyses.

2023-03-11 | PXD038024 | Pride

Identification of protein interactors of SPAG1 in human airway epithelia

Project description:Dysfunctional motile cilia result in primary ciliary dyskinesia (PCD), a genetically heterogeneous disorder characterized by chronic oto-sino-pulmonary disease, infertility, and laterality defects. Mutations in dynein axonemal assembly factors (DNAAF), that facilitate the assembly of dynein arms in the cytoplasm before transport into the cilium, cause PCD. Sperm-associated antigen 1 (SPAG1) is a DNAAF; however, SPAG1’s precise role in dynein assembly is unknown. Here, we identify a novel 60 kDa SPAG1 isoform that can partially compensate for the absence of full-length SPAG1 to assemble normal outer dynein arms, leading to phenotypic variability in PCD subjects with SPAG1 mutations. Our data shows that SPAG1 interacts with DNAAF, dynein chains, and components of the R2TP complex, and SPAG1 is necessary for axonemal dynein arm assembly by facilitating the folding and/or binding of the dynein heavy chains to the intermediate chain complex.

2022-03-20 | PXD032349 | Pride

PCD Longitudinal Prior to 10

Project description:Primary Ciliary Dyskinesia (PCD) is a genetic defect in airway host-defense, and typically results in chronic infection of the airways. Patients with PCD have chronic lung, sinus and ear infections. This longitudinal study is designed to define the rate of progression of PCD lung function in participants prior to 10 years of age using special lung function tests, which help to track lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis [assessed by high-resolution computerized tomography (HRCT) of the chest].

| phs001310 | dbGaP

Longitudinal Study of PCD: 5-18 Years of Age

Project description:The purpose of this longitudinal study protocol is to define age-related prevalence of phenotypic characteristics and the progression of key features of lung disease in participants with one of these disorders, Primary Ciliary Dyskinesia (PCD). In PCD, the abnormal structure and function of cilia results in impaired clearance of secretions and consequent obstruction and chronic recurrent infection in the airways, sinuses and middle ears. Although it seems likely that the onset of PCD airway disease occurs early in childhood, as has been reported for cystic fibrosis (CF), the clinical course of PCD lung disease is not well defined, nor, is the time course of emergence of specific microbial pathogens, or the age of onset and rate of progression of airway disease and bronchiectasis. This longitudinal study is designed to define the rate of progression of PCD lung function in participants between 5-18 years of age using spirometry which tracks well with lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis (assessed by high-resolution computerized tomography, HRCT, of the chest). Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

| phs000596 | dbGaP

Methylation of Ciliary Dynein Motors Involves the Essential Cytosolic Assembly Factor DNAAF3/PF22

Project description:Axonemal dynein motors drive ciliary motility and can consist of up to twenty distinct components with a combined mass of ~2 MDa. In mammals, failure of dyneins to assemble within the axonemal superstructure leads to primary ciliary dyskinesia. Syndromic phenotypes include infertility, rhinitis, severe bronchial conditions, and situs inversus. Nineteen specific cytosolic factors (DNAAFs) are necessary for axonemal dynein assembly although the detailed mechanisms involved remain very unclear. Here we identify the assembly factor DNAAF3 as a structural ortholog of S-adenosyl methionine-dependent methyltransferases. We further demonstrate that dynein heavy chains, especially those forming the ciliary outer arms, are methylated on key residues within various nucleotide-binding sites and on microtubule-binding domain helices directly involved in the transition to low binding affinity. These variable modifications, which are generally missing in a Chlamydomonas null mutant for the DNAAF3 ortholog PF22 (DAB1), likely impact on motor mechanochemistry fine-tuning the activities of individual dynein complexes.

2024-02-12 | PXD045935 | Pride

ZMYND10 functions in a chaperone-relay during axonemal dynein assembly

Project description:Molecular chaperones are abundant cellular proteins that promote the folding, function and macromolecular assembly of a diverse set of substrate proteins, also known as clients. Regulation of chaperone specificity and function involves association with a growing set of distinct cofactors, or cochaperones. How these client, co-chaperone and chaperone interactions in vivo underpin the proteostasis network during development and disease remains unclear. We have combined mouse genetics, imaging and quantitative proteomics to systematically characterize a chaperone-cochaperone-client interaction network in mammalian motile ciliated cells. We uncover ZMYND10 to act as a specificity factor for the immunophilin cochaperone FKBP8 and HSP90 chaperone for the biosynthesis of the heavy chains of axonemal dyneins required for cilial beat. We establish a series of protein-protein interactions during cytoplasmic pre-assembly of macromolecular dynein motors, some of which are directly ZMYND10-dependent. In the absence of ZMYND10, failure of these interactions results in misfolded and unstable dynein heavy chains, which together with non-functional folding intermediates, are targeted for degradation. We propose that the motile ciliopathy Primary Ciliary Dyskinesia (PCD), such as seen in Zmynd10 mutants, be reconsidered as a disorder of protein folding, which opens new avenues for development of therapeutics.

2018-07-12 | PXD006849 | Pride

Genome-wide gene expression analysis in primary ciliary dyskinesia patients

Project description:We performed whole genome gene expression profiling in bronchial biopsies from PCD patients. We used the Quality Threshold clustering algorithm to identify groups of genes that revealed highly correlated RNA expression patterns in the biopsies. The largest cluster contained 372 genes and was significantly enriched for genes related to cilia. The database and literature search showed that 16250 genes in this cluster were known cilia genes, strongly indicating that the remaining 21022 genes were likely to be new cilia genes. The tissue expression pattern of the 210 new cilia genes and the 162 known genes was consistent with the presence of motile cilia in a given tissue. Analysis of the upstream promotor sequences revealed evidence for RFX transcription factors binding site motif in both subgroups. Total RNA obtained from 6 primary ciliary dyskinesia patients and 9 control individuals

2015-02-24 | E-GEOD-25186 | biostudies-arrayexpress

EGAS00001000523-sc-20141204 - samples

Project description:Approximately 80% of clinically clearly diagnosed patients suffering from primary ciliary dyskinesia (PCD) cannot be assigned to a specific gene defect. Despite extensive research on PCD and despite the increasing number of PCD genes and knowledge about their sites of action as e.g structural component or cytoplasmic pre-assembly factor, the biology of motile cilia and the pathomechanism leading to PCD is largely unknown. The aim of this study is to identify novel PCD related genes and processes relevant for motile cilia function. We will perform exome sequencing, aiming on the analysis of family trios. In these families, the diagnosis of PCD is secured, but the underlying gene defects has so far not been identified.

| EGAD00001001092 | EGA

ESGI Identification of novel genes and mechanisms leading to Primary Ciliary Dyskinesia

| EGAS00001000523 | EGA

Paraneoplastic Cerebellar Degeneration (PCD) related ovarian cancer transcriptomic analysis

Project description:To compare transcriptomic data from ovarian cancers related to PCD with anti-Yo antibodies with control ovarian cancers from published data

2017-10-18 | E-MTAB-5942 | biostudies-arrayexpress

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