RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes

Primary ciliary dyskinesia (PCD) is a rare, heterogeneous ciliopathy resulting in chronic oto-sino-pulmonary disease, bronchiectasis, newborn respiratory distress, and laterality defects. PCD diagnosis can be achieved by following diagnostic algorithms that include electron microscopy, genetics, and ancillary testing. Genetic mutations in more than 45 genes, including RSPH4A, can lead to PCD. RSPH4A mutations located on chromosome six, affect radial spokes and results in central complex apparatus abnormalities. The RSPH4A [c.921 + 3_6delAAGT] founder mutation was described as one cause of PCD without laterality defects in Puerto Rico. Additionally, there are further diagnostic challenges present in the Puerto Rican population to diagnose PCD. We describe the demographics, clinical features, and RSPH4A genetic variants in 13 patients with clinical PCD affecting 11 Puerto Ricans from unrelated families.

Download Full-text

Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106424 ◽

2019 ◽

Vol 57 (4) ◽

pp. 237-244 ◽

Cited By ~ 2

Author(s):

Sylvain Blanchon ◽

Marie Legendre ◽

Mathieu Bottier ◽

Aline Tamalet ◽

Guy Montantin ◽

...

Keyword(s):

Primary Ciliary Dyskinesia ◽

High Speed ◽

Genetic Disorder ◽

Beat Frequency ◽

Ciliary Beat Frequency ◽

Central Complex ◽

Ciliary Beating ◽

Recovery Stroke ◽

Biallelic Mutations ◽

Ciliary Dyskinesia

BackgroundPrimary ciliary dyskinesia (PCD) is a rare genetic disorder resulting in abnormal ciliary motility/structure, extremely heterogeneous at genetic and ultrastructural levels. We aimed, in light of extensive genotyping, to identify specific and quantitative ciliary beating anomalies, according to the ultrastructural phenotype.MethodsWe prospectively included 75 patients with PCD exhibiting the main five ultrastructural phenotypes (n=15/group), screened all corresponding PCD genes and measured quantitative beating parameters by high-speed video-microscopy (HSV).ResultsSixty-eight (91%) patients carried biallelic mutations. Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved. ODA defect induces a residual beating with dramatically low ciliary beat frequency (CBF) related to increased recovery stroke and pause durations, especially in case of DNAI1 mutations. IDA defect with microtubular disorganisation induces a low percentage of beating cilia with decreased beating angle and, in case of CCDC39 mutations, a relatively conserved mean CBF with a high maximal CBF. Central complex defect induces nearly normal beating parameters, regardless of the gene involved, and a gyrating motion in a minority of ciliated edges, especially in case of RSPH1 mutations. PCD with normal ultrastructure exhibits heterogeneous HSV values, but mostly an increased CBF with an extremely high maximal CBF.ConclusionQuantitative HSV analysis in PCD objectives beating anomalies associated with specific ciliary ultrastructures and genotypes. It represents a promising approach to guide the molecular analyses towards the best candidate gene(s) to be analysed or to assess the pathogenicity of the numerous sequence variants identified by next-generation-sequencing.

Download Full-text

Loss-of-Function Mutations in RSPH1 Cause Primary Ciliary Dyskinesia with Central-Complex and Radial-Spoke Defects

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2013.07.013 ◽

2013 ◽

Vol 93 (3) ◽

pp. 561-570 ◽

Cited By ~ 91

Author(s):

Esther Kott ◽

Marie Legendre ◽

Bruno Copin ◽

Jean-François Papon ◽

Florence Dastot-Le Moal ◽

...

Keyword(s):

Primary Ciliary Dyskinesia ◽

Central Complex ◽

Loss Of Function ◽

Radial Spoke ◽

Ciliary Dyskinesia

Download Full-text

Structural insights into the cause of human RSPH4A primary ciliary dyskinesia

Molecular Biology of the Cell ◽

10.1091/mbc.e20-12-0806 ◽

2021 ◽

pp. mbc.E20-12-0806

Author(s):

Yanhe Zhao ◽

Justine Pinskey ◽

Jianfeng Lin ◽

Weining Yin ◽

Patrick R. Sears ◽

...

Keyword(s):

Primary Ciliary Dyskinesia ◽

Electron Tomography ◽

Three Dimensional ◽

Dimensional Structure ◽

Structural Basis ◽

Radial Spoke ◽

Radial Spokes ◽

Cilia And Flagella ◽

Tract Infections ◽

Ciliary Dyskinesia

Cilia and flagella are evolutionarily conserved eukaryotic organelles involved in cell motility and signaling. In humans, mutations in Radial Spoke Head Protein 4 homolog A ( RSPH4A) can lead to primary ciliary dyskinesia (PCD), a life-shortening disease characterized by chronic respiratory tract infections, abnormal organ positioning, and infertility. Despite its importance for human health, the location of RSPH4A in human cilia has not been resolved, and the structural basis of RSPH4A-/- PCD remains elusive. Here, we present the native, three-dimensional structure of RSPH4A-/- human respiratory cilia using samples collected non-invasively from a PCD patient. Using cryo-electron tomography and subtomogram averaging, we compared the structures of control and RSPH4A-/- cilia, revealing primary defects in two of the three radial spokes (RSs) within the axonemal repeat and secondary (heterogeneous) defects in the central pair complex. Similar to RSPH1-/- cilia, the radial spoke heads of RS1 and RS2, but not RS3, were missing in RSPH4A-/- cilia. However, RSPH4A-/- cilia also exhibited defects within the arch domains adjacent to the RS1 and RS2 heads, which were not observed with RSPH1 loss. Our results provide insight into the underlying structural basis for RSPH4A-/- PCD and highlight the benefits of applying cryo-ET directly to patient samples for molecular structure determination. [Media: see text]

Download Full-text

Primary ciliary dyskinesia in a Staffordshire bull terrier : clinical communication

Journal of the South African Veterinary Association ◽

10.4102/jsava.v75i3.471 ◽

2004 ◽

Vol 75 (3) ◽

Cited By ~ 5

Author(s):

M. De Scally ◽

R.G. Lobetti ◽

E. Van Wilpe

Keyword(s):

Cross Sections ◽

Primary Ciliary Dyskinesia ◽

Clinical Communication ◽

First Case ◽

Transmission Electron ◽

Radial Spokes ◽

History Of ◽

Tract Infections ◽

Ciliary Dyskinesia ◽

Recurrent Respiratory Tract Infections

Primary ciliary dyskinesia (PCD) is a diverse group of inherited structural and functional abnormalities of the respiratory and other cilia, which results in recurrent respiratory tract infections. Primary ciliary dyskinesia was diagnosed in a 14-week old Staffordshire bull terrier that had a history of respiratory disease from 7 weeks of age. Pneumonia was diagnosed on thoracic radiographs and transtracheal aspirate. Transmission electron microscopy of the bronchi and trachea indicated the presence of both primary and secondary ciliary dyskinesia. The most prominent primary defects consisted of absent inner dyneim arms, absent radial spokes and absence of the central microtubules. These defects accounted for 62 % of the total number of cross-sections screened. Non-specific ciliary abnormalities encountered most often were compound cilia, swollen cilia, addition / deletion of peripheral doublets and disorganised axonemes (26 %). To the authors' knowledge, this is the first case of PCD described in the Staffordshire bull terrier and the first report of PCD in South Africa.

Download Full-text