Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia

Abstract 485: A Mouse Model of Primary Ciliary Dyskinesia Reveals High Frequencies of Heterotaxy and Complex Congenital Heart Defects

Circulation ◽

10.1161/circ.116.suppl_16.ii_83 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Serena Y Tan ◽

Linda Leatherbury ◽

Julie Rosenthal ◽

Xiao-Qing Zhao ◽

Cecilia W Lo

Keyword(s):

Situs Inversus ◽

Primary Ciliary Dyskinesia ◽

Congenital Heart ◽

Heart Defects ◽

Vena Cava ◽

Situs Inversus Totalis ◽

Complex Congenital Heart Disease ◽

Ciliary Function ◽

Situs Solitus ◽

Ciliary Dyskinesia

Specification of left-right asymmetry is essential for formation of the four chamber heart and separate systemic and pulmonary circulation. Previous studies suggest monocilia at the embryonic node is required for left-right patterning. This patterning is perturbed in primary ciliary dyskinesia (PCD) where situs defects and bronchiectasis are observed, often due to ciliary dysfunction arising from dynein mutations. Most PCD patients exhibit situs solitus or situs inversus totalis, but heterotaxy with complex congenital heart disease (CHD) appears to be rare, reported as 6%. We recovered a mouse mutation in dynein Mdnah5 that disrupts ciliary function. Homozygote mutants exhibit situs phenotypes consistent with PCD in humans. To assess the frequency of CHD associated with PCD, we harvested16 litters of embryos. All wildtype and heterozygous offspring (89) showed normal body situs. Of the 21 (19%) homozygous mutants obtained, 6 had situs solitus, 7 situs inversus and 8 heterotaxy, with heterotaxy being any situs deviation in the cardiac, pulmonary or visceral anatomy. Of the heterotaxic embryos, 3 had levo and 5 dextrocardia. Histology and 3D reconstruction showed 7 of the heterotaxy embryos had complex CHD, which included atrial isomerism, superior-inferior ventricles (Figure ), malposition of the great arteries, AV cushion defects, and azygous continuation of the inferior vena cava. These results show a much higher frequency of heterotaxy and complex CHD than previously reported for PCD (38% vs. 6%), suggesting PCD patients should be screened for CHD. The high incidence of CHD associated with PCD indicates ciliary function may have other roles in cardiovascular patterning.

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Mouse model of primary ciliary dyskinesia

Science-Business eXchange ◽

10.1038/scibx.2009.679 ◽

2009 ◽

Vol 2 (16) ◽

pp. 679-679

Keyword(s):

Mouse Model ◽

Primary Ciliary Dyskinesia ◽

Ciliary Dyskinesia

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Looks normal, but may not function properly: A “new” mouse model for primary ciliary dyskinesia

Human Mutation ◽

10.1002/humu.22570 ◽

2012 ◽

Vol 33 (3) ◽

pp. 5-5

Author(s):

Ming Qi

Keyword(s):

Mouse Model ◽

Primary Ciliary Dyskinesia ◽

Ciliary Dyskinesia

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Primary ciliary dyskinesia: a major player in a bigger game

Breathe ◽

10.1183/20734735.0047-2020 ◽

2020 ◽

Vol 16 (2) ◽

pp. 200047

Author(s):

Reena Bhatt ◽

Claire Hogg

Keyword(s):

Primary Ciliary Dyskinesia ◽

Heart Defects ◽

List Type ◽

Loss Of Function ◽

Brush Biopsy ◽

Disease Mechanisms ◽

Major Player ◽

Motile Cilia ◽

Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an inherited disorder of clinical and genetic heterogeneity resulting from mutations in genes involved in the transport, assembly and function of motile cilia. The resulting impairment in mucociliary clearance means patients suffer from chronic progressive lung disease, bronchiectasis, rhinosinusitis and middle ear disease. Subfertility is common to both male and female patients. Situs abnormalities occur in around half of patients, with a subgroup suffering more complex situs arrangements where congenital heart defects or other organ abnormalities frequently coexist. Variations from the classical PCD phenotype are increasingly recognised where overlapping features across a range of motile and nonmotile ciliopathies are redefining our approach to both diagnosis and management of these complex conditions. PCD offers an ideal opportunity for direct visualisation of ciliary function and structure, following nasal brush biopsy, allowing opportunities for researchers to directly interrogate the downstream impact of loss of function mutations. In turn, this has led to rapid advances in the development of new diagnostic tests. These advances mean that PCD is an excellent disease model for understanding the genetic and mechanistic causes of the clinical phenotype for all respiratory ciliopathies. Furthermore, the overlapping role of motile ciliary defects in a wider set of complex and syndromic disorders related to loss of function mutations in primary, nonmotile cilia has been recognised. As we better understand the role of ciliary defects in a broad spectrum of diseases, we should aim to map out a framework through which we can identify, diagnose and treat all respiratory ciliopathies.Key pointsPrimary ciliary dyskinesia is just one of a group of conditions where a heterogeneous array of genetic mutations affect the assembly or structure of motile cilia.Overlapping phenotypes between motile and nonmotile ciliopathies are redefining the diagnostic and therapeutic approach to encompass all ciliopathy patients with a respiratory phenotype.An extended diagnostic algorithm may be required to capture the majority of cases with a respiratory ciliopathy, including patients with syndromic ciliopathies.The terminology around disorders of motile cilia is becoming more descriptive to better reflect the heterogeneity and underlying disease mechanisms across the spectrum of respiratory ciliopathies.Educational aimsTo summarise the existing knowledge base around the disease mechanisms for respiratory ciliopathies, including primary ciliary dyskinesia (PCD).To explore and understand the reasons for changing terminology around respiratory ciliopathies.To emphasise key messages around the diagnosis and treatment of all ciliopathies.Diagnosing PCD is complex and time consuming, and there is no single stand-alone test that can confirm or exclude a diagnosis in all cases.

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Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia

Disease Models & Mechanisms ◽

10.1242/dmm.038489 ◽

2019 ◽

Vol 12 (8) ◽

pp. dmm038489 ◽

Cited By ~ 7

Author(s):

Francesco Chiani ◽

Tiziana Orsini ◽

Alessia Gambadoro ◽

Miriam Pasquini ◽

Sabrina Putti ◽

...

Keyword(s):

Mouse Model ◽

Primary Ciliary Dyskinesia ◽

Functional Loss ◽

Ciliary Dyskinesia

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Evaluation of a Clinical Index as a Predictive Tool for Primary Ciliary Dyskinesia

Diagnostics ◽

10.3390/diagnostics11061088 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1088

Author(s):

Vendula Martinů ◽

Lucie Bořek-Dohalská ◽

Žofia Varényiová ◽

Jiří Uhlík ◽

Václav Čapek ◽

...

Keyword(s):

Primary Ciliary Dyskinesia ◽

Heart Defects ◽

Signs And Symptoms ◽

Roc Curves ◽

Operating Characteristics ◽

Predictive Tool ◽

Clinical Index ◽

Risk Patients ◽

Wet Cough ◽

Ciliary Dyskinesia

Background: In primary ciliary dyskinesia (PCD) there is no single diagnostic test. Different predictive tools have been proposed to guide referral of high-risk patients for further diagnostic workup. We aimed to test clinical index (CI) on a large unselected cohort and compare its characteristics with other widely used tools—PICADAR and NA-CDCF. Methods: CI, PICADAR, and NA-CDCF scores were calculated in 1401 patients with suspected PCD referred to our center. Their predictive characteristics were analyzed using receiver operating characteristics (ROC) curves and compared to each other. Nasal nitric oxide (nNO) was measured in 569 patients older than 3 years. Results: PCD was diagnosed in 67 (4.8%) patients. CI, PICADAR, and NA-CDCF scores were higher in PCD than in nonPCD group (all p < 0.001). The area under the ROC curve (AUC) for CI was larger than for NA-CDCF (p = 0.005); AUCPICADAR and AUCNA-CDCF did not differ (p = 0.093). An overlap in signs and symptoms among tools was identified. PICADAR could not be assessed in 86 (6.1%) patients without chronic wet cough. For CI laterality or congenital heart defects assessment was not necessary. nNO further improved predictive power of all three tools. Conclusion: CI is a feasible predictive tool for PCD that may outperform PICADAR and NA-CFCD.

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