scholarly journals Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1550
Author(s):  
Channa N. Jayasena ◽  
Anu Sironen
Keyword(s):  
Male Fertility ◽  
Primary Ciliary Dyskinesia ◽  
Reproductive Tract ◽  
Respiratory Infections ◽  
Current Knowledge ◽  
Treatment Options ◽  
Heavy Chains ◽  
Sperm Development ◽  
Motile Cilia ◽  
Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD), a disease caused by the malfunction of motile cilia, manifests mainly with chronic recurrent respiratory infections. In men, PCD is also often associated with infertility due to immotile sperm. Since causative mutations for PCD were identified in over 50 genes, the role of these genes in sperm development should be investigated in order to understand the effect of PCD mutations on male fertility. Previous studies showed that different dynein arm heavy chains are present in respiratory cilia and sperm flagellum, which may partially explain the variable effects of mutations on airways and fertility. Furthermore, recent studies showed that male reproductive tract motile cilia may play an important part in sperm maturation and transport. In some PCD patients, extremely low sperm counts were reported, which may be due to motile cilia dysfunction in the reproductive tract rather than problems with sperm development. However, the exact roles of PCD genes in male fertility require additional studies, as do the treatment options. In this review, we discuss the diagnostic and treatment options for men with PCD based on the current knowledge.

scholarly journals Wampa is a dynein subunit required for axonemal assembly and male fertility in Drosophila

2019 ◽  
Author(s):  
Elisabeth Bauerly ◽  
Kexi Yi ◽  
Matthew C. Gibson
Keyword(s):  
Male Fertility ◽  
Primary Ciliary Dyskinesia ◽  
Functional Role ◽  
Essential Role ◽  
Respiratory Infections ◽  
Pathological Features ◽  
Dynein Arms ◽  
Cilia And Flagella ◽  
Ciliary Dyskinesia

AbstractAxonemal dyneins are motor proteins that form the inner and outer arms of the axoneme in cilia and flagella. Defects in dynein arms are the leading cause of primary ciliary dyskinesia (PCD), which is characterized by chronic respiratory infections, situs inversus, and sterility. Despite current understanding of pathological features associated with PCD, many of their causative genes still remain elusive. Here we analyze genetic requirements for wampa (wam), a previously uncharacterized component of the outer dynein arm that is essential for male fertility. In addition to a role in outer dynein arm formation, we uncovered additional requirements during spermatogenesis, including regulation of remodeling events for the mitochondria and the nucleus. Due to the conserved nature of axonemal dyneins and their essential role in both PCD and fertility, this study advances our understanding of the pathology of PCD, as well as the functional role of dyneins in axonemal formation and spermatogenesis.

scholarly journals Unique among ciliopathies: primary ciliary dyskinesia, a motile cilia disorder

2015 ◽  
Vol 7 ◽  
Author(s):  
Kavita Praveen ◽  
Erica E. Davis ◽  
Nicholas Katsanis
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Motile Cilia ◽  
Ciliary Dyskinesia

scholarly journals Gene discovery for motile cilia disorders: mutation spectrum in primary ciliary dyskinesia and discovery of mutations in CCDC151

Cilia ◽  
2015 ◽  
Vol 4 (Suppl 1) ◽  
pp. P30
Author(s):  
A Onoufriadis ◽  
R Hjeij ◽  
CM Watson ◽  
CE Slagle ◽  
NT Klena ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Gene Discovery ◽  
Mutation Spectrum ◽  
Motile Cilia ◽  
Ciliary Dyskinesia

scholarly journals A novel hypomorphic allele of Spag17 causes primary ciliary dyskinesia phenotypes in mice

2020 ◽  
Vol 13 (10) ◽  
pp. dmm045344
Author(s):  
Zakia Abdelhamed ◽  
Marshall Lukacs ◽  
Sandra Cindric ◽  
Heymut Omran ◽  
Rolf W. Stottmann
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Primary Ciliary Dyskinesia ◽  
Human Condition ◽  
Central Pair ◽  
Cerebrospinal Fluid Flow ◽  
Hypomorphic Allele ◽  
Motile Cilia ◽  
The Brain ◽  
Ciliary Dyskinesia

ABSTRACTPrimary ciliary dyskinesia (PCD) is a human condition of dysfunctional motile cilia characterized by recurrent lung infection, infertility, organ laterality defects and partially penetrant hydrocephalus. We recovered a mouse mutant from a forward genetic screen that developed many of the hallmark phenotypes of PCD. Whole-exome sequencing identified this primary ciliary dyskinesia only (Pcdo) allele to be a nonsense mutation (c.5236A>T) in the Spag17 coding sequence creating a premature stop codon (K1746*). The Pcdo variant abolished several isoforms of SPAG17 in the Pcdo mutant testis but not in the brain. Our data indicate differential requirements for SPAG17 in different types of motile cilia. SPAG17 is essential for proper development of the sperm flagellum and is required for either development or stability of the C1 microtubule structure within the central pair apparatus of the respiratory motile cilia, but not the brain ependymal cilia. We identified changes in ependymal ciliary beating frequency, but these did not appear to alter lateral ventricle cerebrospinal fluid flow. Aqueductal stenosis resulted in significantly slower and abnormally directed cerebrospinal fluid flow, and we suggest that this is the root cause of the hydrocephalus. The Spag17Pcdo homozygous mutant mice are generally viable to adulthood but have a significantly shortened lifespan, with chronic morbidity. Our data indicate that the c.5236A>T Pcdo variant is a hypomorphic allele of Spag17 that causes phenotypes related to motile, but not primary, cilia. Spag17Pcdo is a useful new model for elucidating the molecular mechanisms underlying central pair PCD pathogenesis in the mouse.This article has an associated First Person interview with the first author of the paper.

scholarly journals COVID-19 vaccinations: perceptions and behaviours in people with primary ciliary dyskinesia

2021 ◽  
Author(s):  
Eva Sophie Lunde Pedersen ◽  
Maria Christina Mallet ◽  
Yin Ting Lam ◽  
Sara Bellu ◽  
Isabelle Cizeau ◽  
...  
Keyword(s):  
Side Effects ◽  
Support Groups ◽  
Primary Ciliary Dyskinesia ◽  
Respiratory Infections ◽  
Public Information ◽  
Social Contact ◽  
Vaccine Uptake ◽  
Vaccination Uptake ◽  
Contact Behaviour ◽  
Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at high risk of severe COVID-19 and vaccination against SARS-CoV-2 is therefore important. We studied vaccination willingness, speed of vaccination uptake, side effects, and changes in social contact behavior after vaccination in people with PCD. We used data from COVID-PCD, an international participatory cohort study. A questionnaire was e-mailed to participants in May 2021 that asked about COVID-19 vaccinations. 423 participants from 31 countries replied (median age: 30 years; 261 (62%) female). Vaccination uptake and willingness was high with 273 of 287 adults (96%) being vaccinated or willing to be in June 2021; only 4% were hesitant. The most common reasons for hesitancy were fear of side effects (reported by 88%). Mild side effects were common but no participant reported severe side effects. Half of participants changed their social contact behaviour after vaccination by seeing friends and family more often. The high vaccination willingness in the study population might reflect the extraordinary effort taken by PCD support groups to inform people about COVID-19 vaccination. Clear and specific public information and involvement of representatives is important for high vaccine uptake.

scholarly journals The Drosophila orthologue of the primary ciliary dyskinesia-associated gene, DNAAF3, is required for axonemal dynein assembly

2021 ◽  
Author(s):  
Petra zur Lage ◽  
Zhiyan Xi ◽  
Jennifer Lennon ◽  
Iain Hunter ◽  
Wai Kit Chan ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Cell Types ◽  
Drosophila Cell ◽  
Heavy Chains ◽  
Neuron Response ◽  
Dynein Motor ◽  
Assembly Factor ◽  
Axonemal Dynein ◽  
Dynein Arms ◽  
Ciliary Dyskinesia

Ciliary motility is powered by a suite of highly conserved axoneme-specific dynein motor complexes. In humans the impairment of these motors through mutation results in the disease, Primary Ciliary Dyskinesia (PCD). Studies in Drosophila have helped to validate several PCD genes whose products are required for cytoplasmic pre-assembly of axonemal dynein motors. Here we report the characterisation of the Drosophila homologue of the less known assembly factor, DNAAF3. This gene, CG17669 (Dnaaf3), is expressed exclusively in developing mechanosensory chordotonal (Ch) neurons and spermatocytes, the only two Drosophila cell types bearing motile cilia/flagella. Mutation of Dnaaf3 results in larvae that are deaf and adults that are uncoordinated, indicating defective Ch neuron function. The mutant Ch neuron cilia of the antenna specifically lack dynein arms, while Ca imaging in larvae reveals a complete loss of Ch neuron response to vibration stimulus, confirming that mechanotransduction relies on ciliary dynein motors. Mutant males are infertile with immotile sperm whose flagella lack dynein arms and show axoneme disruption. Analysis of proteomic changes suggest a reduction in heavy chains of all axonemal dynein forms, consistent with an impairment of dynein pre-assembly.

scholarly journals Frequency and Types of Ciliary Ultrastructural Defects in Patients With Suspected Primary Ciliary Dyskinesia Symptoms Analyzed by Transmission Electron Microscopy

2021 ◽  
Author(s):  
Mitra Rezaei ◽  
Amirali Soheili ◽  
Atefeh Fakharian ◽  
Hamid Jamaati ◽  
Jahangir Ghorbani ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Primary Ciliary Dyskinesia ◽  
Respiratory Infections ◽  
Descriptive Analysis ◽  
Final Diagnosis ◽  
International Consensus ◽  
Tem Analysis ◽  
Transmission Electron ◽  
Ciliary Dyskinesia

Abstract Background: Primary ciliary dyskinesia (PCD) is a rare autosomal recessive condition of often chronic respiratory infections in early life. A useful tool for early diagnosis of such ciliary abnormalities is transmission electron microscopy (TEM). This study aimed to use TEM to examine these defects and speculate on a diagnosis.Methods: From 2017 to 2019, all referral patients with suspected PCD symptoms were included in this study. Nasal samples were taken after exclusion of further potential differential diagnosis and prepared for TEM. The final diagnosis was based on the International Consensus Guideline for reporting transmission electron microscopy results in the diagnosis of PCD. A descriptive analysis of demographic and ciliary ultrastructural data was performed by SPSS ver 21.Results: Study population consisted of 37 women and 30 men (mean age=20.34±10.7 years). The clinical presentations were as follows: bronchiectasis: 26 patients (38.8%); sinusitis: 23(34.3%); recurrent respiratory infection: 21 patients (31.3%); auditory symptoms: 5 patients (7.5%); situs inversus: 3 patients (4.4%); productive cough: 2 patients (3%); infertility: 2 patients (3%); polyposis: 1 patient (1.5%). According to TEM analysis, 12 (17%) of patients were PCD, 11 (15.7%) were indicating PCD cases, 26 (37.1%) of them had no criteria of PCD and 18 (25.7%) of cases had normal ciliary ultrastructure. Compound cilia and extra-tubule were reported in 29 (41.4%) and 31(44.3%) of patients, respectively. The outer dynein arm defect was seen in 11(16.4%) cases and the inner dynein arm (IDA) defect was seen in 20 (29.8%) cases. Two patients (3%) had microtubular disorganization.Conclusion: Bronchiectasis and sinusitis were the most common complications. The compound cilia and extra-tubule were the most prevalent TEM finding among all participants. However, the most prevalent hallmark diagnostic defects among PCD patients were ODA and IDA defects among PCD patients. Other diagnostic PCD tests should also be performed in patients in the indicating PCD group, those without PCD criteria, and normal patients with a highly suggestive history. Cell-culture, as well, should confirm IDA defects. This study highlights the fundamental need to consider ciliary defect among probable diagnoses and use TEM as a practical diagnostic tool.

scholarly journals TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella

2020 ◽  
Vol 106 (2) ◽  
pp. 153-169 ◽  
Author(s):  
Lucie Thomas ◽  
Khaled Bouhouche ◽  
Marjorie Whitfield ◽  
Guillaume Thouvenin ◽  
Andre Coste ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Loss Of Function ◽  
Motile Cilia ◽  
Ciliary Dyskinesia

scholarly journals Impaired Growth during Childhood in Patients with Primary Ciliary Dyskinesia

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Tamara Svobodová ◽  
Jana Djakow ◽  
Daniela Zemková ◽  
Adam Cipra ◽  
Petr Pohunek ◽  
...  
Keyword(s):  
Body Length ◽  
Primary Ciliary Dyskinesia ◽  
Respiratory Infections ◽  
Growth Period ◽  
Growth Delay ◽  
Childhood Growth ◽  
Population Standards ◽  
Children And Young Adults ◽  
Nutritional Deficits ◽  
Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) leads to recurrent/chronic respiratory infections, resulting in chronic inflammation and potentially in chronic pulmonary disease with bronchiectasis. We analyzed longitudinal data on body length/height and body mass index (BMI) for 29 children and young adults with PCD aging 1.5–24 years (median, 14.5) who had been diagnosed at the age of 0.5–17 years (median, 8). Of these, 10 carried pathogenic mutations in eitherDNAH5orDNAI1. In children with PCD, body length/height progressively decreased from+0.40±0.24SDS (the 1st birthday),+0.16±0.23SDS (3 years old), and-0.13±0.21SDS (5 years old) to-0.54±0.19SDS (7 years old;P=0.01versus0),-0.67±0.21SDS (9 years old;P=0.005versus0),-0.52±0.24SDS (11 years old;P=0.04versus0), and-0.53±0.23SDS (13 years old;P=0.03versus0). These results reflect low growth rates during the childhood growth period. Thereafter, heights stabilized up to the age of 17 years. The growth deterioration was not dependent on sex or disease severity but was more pronounced inDNAH5orDNAI1mutation carriers. BMI did not differ from population standards, which suggests that nutritional deficits are not the cause of growth delay. We conclude that PCD leads to chronic deprivation with significant growth deterioration during childhood.

scholarly journals Mutation of CFAP57 causes primary ciliary dyskinesia by disrupting the asymmetric targeting of a subset of ciliary inner dynein arms

2019 ◽  
Author(s):  
Ximena M. Bustamante-Marin ◽  
Amjad Horani ◽  
Mihaela Stoyanova ◽  
Wu-Lin Charng ◽  
Mathieu Bottier ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Primary Ciliary Dyskinesia ◽  
Large Population ◽  
Exome Capture ◽  
Swimming Velocity ◽  
Population Sampling ◽  
Dynein Arms ◽  
Motile Cilia ◽  
Ciliary Dyskinesia ◽  
Sampling Probability

AbstractPrimary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis, and is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious TEM structural phenotype for pathogenic variants using whole exome capture and next generation sequencing. The population sampling probability (PSAP) algorithm identified one subject with a homozygous nonsense variant [(c.1762C>T) p.(Arg588*) exon 11] in the uncharacterized CFAP57 gene. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Analysis of cells from the PCD patient shows a loss of CFAP57, reduced beat frequency, and an alteration in the ciliary waveform. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is conserved in organisms that assemble motile cilia, and CFAP57 is allelic with the BOP2 gene identified previously in Chlamydomonas. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass spectroscopy showed that CFAP57 is missing, and the “g” inner dyneins (DHC7 and DHC3) and the “d” inner dynein (DHC2) are reduced. Our data demonstrate that the FAP57 protein is required for the asymmetric assembly of inner dyneins on only a subset of the microtubule doublets, and this asymmetry is essential for the generation of an effective axonemal waveform. Together, our data identifies mutations in CFAP57 as a cause of PCD with a specific defect in the inner dynein arm assembly process.SignificanceMotile cilia are found throughout eukaryotic organisms and performs essential functions. Primary ciliary dyskinesia (PCD) is a rare disease that affects the function of motile cilia. By applying a novel population sampling probability algorithm (PSAP) that uses large population sequencing databases and pathogenicity prediction algorithms, we identified a variant in an uncharacterized gene, CFAP57. This is the first reported example of PCD caused by a mutation that affects only a subset of the inner dynein arms, which are needed to generate the waveform. CFAP57 identifies an address for specific dynein arms. These findings demonstrate the effectiveness of the PSAP algorithm, expand our understanding of the positioning of dynein arms, and identify mutations in CFAP57 as a cause of PCD.

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