International Journal of Molecular Sciences

Editorial

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4 pages, 198 KiB

Open AccessEditorial

Perspectives for Primary Ciliary Dyskinesia

by Zuzanna Bukowy-Bieryllo, Michal Witt and Ewa Zietkiewicz

Int. J. Mol. Sci. 2022, 23(8), 4122; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084122 - 08 Apr 2022

Cited by 3 | Viewed by 1719

Abstract

Primary ciliary dyskinesia (PCD) is a ciliopathy caused by genetically determined impairment of motile cilia–organelles present on the surface of many types of cells [...] Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

Research

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17 pages, 13211 KiB

Open AccessArticle

Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype

by Lawrence E. Ostrowski, Weining Yin, Amanda J. Smith, Patrick R. Sears, Ximena M. Bustamante-Marin, Hong Dang, Friedhelm Hildebrandt, Leigh Anne Daniels, Nicole A. Capps, Kelli M. Sullivan, Margaret W. Leigh, Maimoona A. Zariwala and Michael R. Knowles

Int. J. Mol. Sci. 2022, 23(3), 1753; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031753 - 03 Feb 2022

Cited by 6 | Viewed by 2348

Abstract

Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, [...] Read more.

Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in > 50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of ODAD1 (CCDC114), a component of the outer dynein arm docking complex, results in a failure to assemble outer dynein arms (ODAs), mostly immotile cilia, and a typical PCD phenotype. We identified a female (now 34 years old) with an unusually mild clinical phenotype who has a homozygous non-canonical splice mutation (c.1502+5G>A) in ODAD1. To investigate the mechanism for the unusual phenotype, we performed molecular and functional studies of cultured nasal epithelial cells. We demonstrate that this splice mutation results in the expression of a truncated protein that is attached to the axoneme, indicating that the mutant protein retains partial function. This allows for the assembly of some ODAs and a significant level of ciliary activity that may result in the atypically mild clinical phenotype. The results also suggest that partial restoration of ciliary function by therapeutic agents could lead to significant improvement of disease symptoms. Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

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17 pages, 1841 KiB

Open AccessArticle

Identification and Classification of Novel Genetic Variants: En Route to the Diagnosis of Primary Ciliary Dyskinesia

by Nina Stevanovic, Anita Skakic, Predrag Minic, Aleksandar Sovtic, Maja Stojiljkovic, Sonja Pavlovic and Marina Andjelkovic

Int. J. Mol. Sci. 2021, 22(16), 8821; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168821 - 17 Aug 2021

Cited by 4 | Viewed by 2403

Abstract

Primary ciliary dyskinesia (PCD) is a disease caused by impaired function of motile cilia. PCD mainly affects the lungs and reproductive organs. Inheritance is autosomal recessive and X-linked. PCD patients have diverse clinical manifestations, thus making the establishment of proper diagnosis challenging. The [...] Read more.

Primary ciliary dyskinesia (PCD) is a disease caused by impaired function of motile cilia. PCD mainly affects the lungs and reproductive organs. Inheritance is autosomal recessive and X-linked. PCD patients have diverse clinical manifestations, thus making the establishment of proper diagnosis challenging. The utility of next-generation sequencing (NGS) technology for diagnostic purposes allows for better understanding of the PCD genetic background. However, identification of specific disease-causing variants is difficult. The main aim of this study was to create a unique guideline that will enable the standardization of the assessment of novel genetic variants within PCD-associated genes. The designed pipeline consists of three main steps: (1) sequencing, detection, and identification of genes/variants; (2) classification of variants according to their effect; and (3) variant characterization using in silico structural and functional analysis. The pipeline was validated through the analysis of the variants detected in a well-known PCD disease-causing gene (DNAI1) and the novel candidate gene (SPAG16). The application of this pipeline resulted in identification of potential disease-causing variants, as well as validation of the variants pathogenicity, through their analysis on transcriptional, translational, and posttranslational levels. The application of this pipeline leads to the confirmation of PCD diagnosis and enables a shift from candidate to PCD disease-causing gene. Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

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17 pages, 12321 KiB

Open AccessArticle

Zebrafish Motile Cilia as a Model for Primary Ciliary Dyskinesia

by Andreia L. Pinto, Margarida Rasteiro, Catarina Bota, Sara Pestana, Pedro Sampaio, Claire Hogg, Thomas Burgoyne and Susana S. Lopes

Int. J. Mol. Sci. 2021, 22(16), 8361; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168361 - 04 Aug 2021

Cited by 7 | Viewed by 3574

Abstract

Zebrafish is a vertebrate teleost widely used in many areas of research. As embryos, they develop quickly and provide unique opportunities for research studies owing to their transparency for at least 48 h post fertilization. Zebrafish have many ciliated organs that include primary [...] Read more.

Zebrafish is a vertebrate teleost widely used in many areas of research. As embryos, they develop quickly and provide unique opportunities for research studies owing to their transparency for at least 48 h post fertilization. Zebrafish have many ciliated organs that include primary cilia as well as motile cilia. Using zebrafish as an animal model helps to better understand human diseases such as Primary Ciliary Dyskinesia (PCD), an autosomal recessive disorder that affects cilia motility, currently associated with more than 50 genes. The aim of this study was to validate zebrafish motile cilia, both in mono and multiciliated cells, as organelles for PCD research. For this purpose, we obtained systematic high-resolution data in both the olfactory pit (OP) and the left–right organizer (LRO), a superficial organ and a deep organ embedded in the tail of the embryo, respectively. For the analysis of their axonemal ciliary structure, we used conventional transmission electron microscopy (TEM) and electron tomography (ET). We characterised the wild-type OP cilia and showed, for the first time in zebrafish, the presence of motile cilia (9 + 2) in the periphery of the pit and the presence of immotile cilia (still 9 + 2), with absent outer dynein arms, in the centre of the pit. In addition, we reported that a central pair of microtubules in the LRO motile cilia is common in zebrafish, contrary to mouse embryos, but it is not observed in all LRO cilia from the same embryo. We further showed that the outer dynein arms of the microtubular doublet of both the OP and LRO cilia are structurally similar in dimensions to the human respiratory cilia at the resolution of TEM and ET. We conclude that zebrafish is a good model organism for PCD research but investigators need to be aware of the specific physical differences to correctly interpret their results. Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

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18 pages, 2532 KiB

Open AccessArticle

The Antimicrobial Activity of Peripheral Blood Neutrophils Is Altered in Patients with Primary Ciliary Dyskinesia

by Maaike Cockx, Marfa Blanter, Mieke Gouwy, Pieter Ruytinx, Sara Abouelasrar Salama, Sofie Knoops, Noëmie Pörtner, Lotte Vanbrabant, Natalie Lorent, Mieke Boon and Sofie Struyf

Int. J. Mol. Sci. 2021, 22(12), 6172; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126172 - 08 Jun 2021

Cited by 7 | Viewed by 2546

Abstract

The airways of patients with primary ciliary dyskinesia (PCD) contain persistently elevated neutrophil numbers and CXCL8 levels. Despite their abundance, neutrophils fail to clear the airways from bacterial infections. We investigated whether neutrophil functions are altered in patients with PCD. Neutrophils from patients [...] Read more.

The airways of patients with primary ciliary dyskinesia (PCD) contain persistently elevated neutrophil numbers and CXCL8 levels. Despite their abundance, neutrophils fail to clear the airways from bacterial infections. We investigated whether neutrophil functions are altered in patients with PCD. Neutrophils from patients and healthy controls (HC) were isolated from peripheral blood and exposed to various bacterial stimuli or cytokines. Neutrophils from patients with PCD were less responsive to low levels of fMLF in three different chemotaxis assays (p < 0.05), but expression of the fMLF receptors was unaltered. PCD neutrophils showed normal phagocytic function and expression of adhesion molecules. However, PCD neutrophils produced less reactive oxygen species upon stimulation with bacterial products or cytokines compared to HC neutrophils (p < 0.05). Finally, the capacity to release DNA, as observed during neutrophil extracellular trap formation, seemed to be reduced in patients with PCD compared to HC (p = 0.066). These results suggest that peripheral blood neutrophils from patients with PCD, in contrast to those of patients with cystic fibrosis or COPD, do not show features of over-activation, neither on baseline nor after stimulation. If these findings extend to lung-resident neutrophils, the reduced neutrophil activity could possibly contribute to the recurrent respiratory infections in patients with PCD. Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

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14 pages, 3436 KiB

Open AccessArticle

Semi-Lethal Primary Ciliary Dyskinesia in Rats Lacking the Nme7 Gene

by Lucie Šedová, Ivana Buková, Pavla Bažantová, Silvia Petrezsélyová, Jan Prochazka, Elena Školníková, Dagmar Zudová, Josef Včelák, Pavol Makovický, Běla Bendlová, Ondřej Šeda and Radislav Sedlacek

Int. J. Mol. Sci. 2021, 22(8), 3810; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083810 - 07 Apr 2021

Cited by 7 | Viewed by 2337

Abstract

NME7 (non-metastatic cells 7, nucleoside diphosphate kinase 7) is a member of a gene family with a profound effect on health/disease status. NME7 is an established member of the ciliome and contributes to the regulation of the microtubule-organizing center. We aimed to create [...] Read more.

NME7 (non-metastatic cells 7, nucleoside diphosphate kinase 7) is a member of a gene family with a profound effect on health/disease status. NME7 is an established member of the ciliome and contributes to the regulation of the microtubule-organizing center. We aimed to create a rat model to further investigate the phenotypic consequences of Nme7 gene deletion. The CRISPR/Cas9 nuclease system was used for the generation of Sprague Dawley Nme7 knock-out rats targeting the exon 4 of the Nme7 gene. We found the homozygous Nme7 gene deletion to be semi-lethal, as the majority of SD^Nme7^−/− pups died prior to weaning. The most prominent phenotypes in surviving SD^Nme7^−/− animals were hydrocephalus, situs inversus totalis, postnatal growth retardation, and sterility of both sexes. Thinning of the neocortex was histologically evident at 13.5 day of gestation, dilation of all ventricles was detected at birth, and an external sign of hydrocephalus, i.e., doming of the skull, was usually apparent at 2 weeks of age. Heterozygous SD^Nme7^+/− rats developed normally; we did not detect any symptoms of primary ciliary dyskinesia. The transcriptomic profile of liver and lungs corroborated the histological findings, revealing defects in cell function and viability. In summary, the knock-out of the rat Nme7 gene resulted in a range of conditions consistent with the presentation of primary ciliary dyskinesia, supporting the previously implicated role of the centrosomally located Nme7 gene in ciliogenesis and control of ciliary transport. Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

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Review

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29 pages, 1956 KiB

Open AccessReview

PCD Genes—From Patients to Model Organisms and Back to Humans

by Michal Niziolek, Marta Bicka, Anna Osinka, Zuzanna Samsel, Justyna Sekretarska, Martyna Poprzeczko, Rafal Bazan, Hanna Fabczak, Ewa Joachimiak and Dorota Wloga

Int. J. Mol. Sci. 2022, 23(3), 1749; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031749 - 03 Feb 2022

Cited by 8 | Viewed by 3386

Abstract

Primary ciliary dyskinesia (PCD) is a hereditary genetic disorder caused by the lack of motile cilia or the assembxly of dysfunctional ones. This rare human disease affects 1 out of 10,000–20,000 individuals and is caused by mutations in at least 50 genes. The [...] Read more.

Primary ciliary dyskinesia (PCD) is a hereditary genetic disorder caused by the lack of motile cilia or the assembxly of dysfunctional ones. This rare human disease affects 1 out of 10,000–20,000 individuals and is caused by mutations in at least 50 genes. The past twenty years brought significant progress in the identification of PCD-causative genes and in our understanding of the connections between causative mutations and ciliary defects observed in affected individuals. These scientific advances have been achieved, among others, due to the extensive motile cilia-related research conducted using several model organisms, ranging from protists to mammals. These are unicellular organisms such as the green alga Chlamydomonas, the parasitic protist Trypanosoma, and free-living ciliates, Tetrahymena and Paramecium, the invertebrate Schmidtea, and vertebrates such as zebrafish, Xenopus, and mouse. Establishing such evolutionarily distant experimental models with different levels of cell or body complexity was possible because both basic motile cilia ultrastructure and protein composition are highly conserved throughout evolution. Here, we characterize model organisms commonly used to study PCD-related genes, highlight their pros and cons, and summarize experimental data collected using these models. Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

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16 pages, 309 KiB

Open AccessReview

Current and Future Treatments in Primary Ciliary Dyskinesia

by Tamara Paff, Heymut Omran, Kim G. Nielsen and Eric G. Haarman

Int. J. Mol. Sci. 2021, 22(18), 9834; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189834 - 11 Sep 2021

Cited by 43 | Viewed by 9630

Abstract

Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes [...] Read more.

Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy. Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

15 pages, 1199 KiB

Open AccessReview

Emerging Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia

by Steven K Brennan, Thomas W Ferkol and Stephanie D Davis

Int. J. Mol. Sci. 2021, 22(15), 8272; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158272 - 31 Jul 2021

Cited by 28 | Viewed by 3661

Abstract

Primary ciliary dyskinesia (PCD) is a rare inherited condition affecting motile cilia and leading to organ laterality defects, recurrent sino-pulmonary infections, bronchiectasis, and severe lung disease. Research over the past twenty years has revealed variability in clinical presentations, ranging from mild to more [...] Read more.

Primary ciliary dyskinesia (PCD) is a rare inherited condition affecting motile cilia and leading to organ laterality defects, recurrent sino-pulmonary infections, bronchiectasis, and severe lung disease. Research over the past twenty years has revealed variability in clinical presentations, ranging from mild to more severe phenotypes. Genotype and phenotype relationships have emerged. The increasing availability of genetic panels for PCD continue to redefine these genotype-phenotype relationships and reveal milder forms of disease that had previously gone unrecognized. Full article

(This article belongs to the Special Issue Primary Ciliary Dyskinesia: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

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