Rare Human Diseases: Model Organisms in Deciphering the Molecular Basis of Primary Ciliary Dyskinesia

Poprzeczko, Martyna; Bicka, Marta; Farahat, Hanan; Bazan, Rafał; Osinka, Anna; Fabczak, Hanna; Joachimiak, Ewa; Włoga, Dorota

doi:10.3390/cells8121614

Cited by 27 publications

(23 citation statements)

References 245 publications

(327 reference statements)

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“…In humans, mutations in several genes encoding components of the CA cause primary ciliary dyskinesia (PCD) or more frequently, multiple morphological abnormalities of the sperm flagella (MMAF) syndrome 33 , 34 . Recent genetic analysis using whole-exome sequencing identified homozygous stop-gain mutation in CFAP69 (p.Gln255X 35 ) and SPEF2 (p.Arg304X 36 ) as likely MMAF causal mutations.…”

Section: Resultsmentioning

confidence: 99%

Composition and function of the C1b/C1f region in the ciliary central apparatus

Joachimiak

Osinka

Farahat

et al. 2021

Sci Rep

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Motile cilia are ultrastructurally complex cell organelles with the ability to actively move. The highly conserved central apparatus of motile 9 × 2 + 2 cilia is composed of two microtubules and several large microtubule-bound projections, including the C1b/C1f supercomplex. The composition and function of C1b/C1f subunits has only recently started to emerge. We show that in the model ciliate Tetrahymena thermophila, C1b/C1f contains several evolutionarily conserved proteins: Spef2A, Cfap69, Cfap246/LRGUK, Adgb/androglobin, and a ciliate-specific protein Tt170/TTHERM_00205170. Deletion of genes encoding either Spef2A or Cfap69 led to a loss of the entire C1b projection and resulted in an abnormal vortex motion of cilia. Loss of either Cfap246 or Adgb caused only minor alterations in ciliary motility. Comparative analyses of wild-type and C1b-deficient mutant ciliomes revealed that the levels of subunits forming the adjacent C2b projection but not C1d projection are greatly reduced, indicating that C1b stabilizes C2b. Moreover, the levels of several IFT and BBS proteins, HSP70, and enzymes that catalyze the final steps of the glycolytic pathway: enolase ENO1 and pyruvate kinase PYK1, are also reduced in the C1b-less mutants.

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Section: Resultsmentioning

confidence: 99%

Composition and function of the C1b/C1f region in the ciliary central apparatus

Joachimiak

Osinka

Farahat

et al. 2021

Sci Rep

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“…В настоящее время терапевтические стратегии ПЦД основаны на утвержденных клинических рекомендациях [67]. Во многих странах за основу терапии пациентов с первичной цилиарной дискинезией взяты протоколы лечения пациентов с муковисцидозом, несмотря на очевидные различия этих заболеваний.…”

Section: терапевтическая стратегияunclassified

Primary ciliary dyskinesia: state of the problem and prospects

Novak

Мизерницкий

2021

Medicinskij sovet

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This review article provides an up-to-date understanding of primary ciliary dyskinesia (immotile-cilia syndrome) and its particular variant, Cartagener syndrome, a genetically determined pathology leading to chronic inflammatory lesions of the respiratory tract, hearing organs, and impaired fertile function. This orphan disease is not well known to the general medical community. Primary ciliary dyskinesia is a rare hereditary disease of the group of ciliopathies that is based on a genetically determined defect in the ultrastructure of the cilia of the respiratory tract epithelium and similar structures, leading to impaired motor function. Various step-by-step algorithms have been proposed to verify the diagnosis, the obligatory components of which are assessment of the motor ability of the cilia of the atopic epithelium, nasal nitric oxide (nNO) level, electron microscopic examination of a bronchial mucosal biopsy specimen, and genetic examination. There is no gold standard for diagnosis of primary ciliary dyskinesia. Diagnostic search in patients should be complex and consist of certain stages. Currently, therapeutic strategies for primary ciliary dyskinesia are based on approved clinical guidelines. In many countries, the therapy of patients with primary ciliary dyskinesia is based on treatment protocols for patients with cystic fibrosis, despite the obvious differences in these diseases. The main goal of therapy is adequate airway clearance, control and prevention of infectious diseases, and elimination of potential airway exposure to various types of pollutants, including tobacco smoke. The article describes the clinic, characteristic symptoms of the disease, its prevalence and genetic aspects, discusses the problems of diagnosis, treatment, prognosis and monitoring of these children, as well as the need for a national register of patients with this pathology.

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“…Together, these challenges reveal a pressing need to couple candidate gene discovery with functional analysis, preferably in a high‐throughput model system to quickly eliminate false positives. We then study the function of new proteins in embryogenesis to improve our understanding of the underlying disease mechanisms, helping to explain the patient phenotype (Blum & Ott, 2018; Duncan & Khokha, 2016; Hwang, Marquez, & Khokha, 2019; Poprzeczko et al, 2019; Shi, Su, Lipschutz, & Lobo, 2017; Z. Song, Zhang, Jia, Yelick, & Zhao, 2016).…”

Section: Introductionmentioning

confidence: 99%

Xenopus to the rescue: A model to validate and characterize candidate ciliopathy genes

Rao

Kulkarni

2021

Genesis

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Summary Cilia are present on most vertebrate cells and play a central role in development, growth, and homeostasis. Thus, cilia dysfunction can manifest into an array of diseases, collectively termed ciliopathies, affecting millions of lives worldwide. Yet, our understanding of the gene regulatory networks that control cilia assembly and functions remain incomplete. With the advances in next‐generation sequencing technologies, we can now rapidly predict pathogenic variants from hundreds of ciliopathy patients. While the pace of candidate gene discovery is exciting, most of these genes have never been previously implicated in cilia assembly or function. This makes assigning the disease causality difficult. This review discusses how Xenopus, a genetically tractable and high‐throughput vertebrate model, has played a central role in identifying, validating, and characterizing candidate ciliopathy genes. The review is focused on multiciliated cells (MCCs) and diseases associated with MCC dysfunction. MCCs harbor multiple motile cilia on their apical surface to generate extracellular fluid flow inside the airway, the brain ventricles, and the oviduct. In Xenopus, these cells are external and present on the embryonic epidermal epithelia, facilitating candidate genes analysis in MCC development in vivo. The ability to introduce patient variants to study their effects on disease progression makes Xenopus a powerful model to improve our understanding of the underlying disease mechanisms and explain the patient phenotype.

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Rare Human Diseases: Model Organisms in Deciphering the Molecular Basis of Primary Ciliary Dyskinesia

Cited by 27 publications

References 245 publications

Composition and function of the C1b/C1f region in the ciliary central apparatus

Composition and function of the C1b/C1f region in the ciliary central apparatus

Primary ciliary dyskinesia: state of the problem and prospects

Xenopus to the rescue: A model to validate and characterize candidate ciliopathy genes

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