Mutation of serine/threonine protein kinase 36 ( STK36 ) causes primary ciliary dyskinesia with a central pair defect

2017 ◽  
Vol 38 (8) ◽  
pp. 964-969 ◽  
Author(s):  
Christine Edelbusch ◽  
Sandra Cindrić ◽  
Gerard W. Dougherty ◽  
Niki T. Loges ◽  
Heike Olbrich ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Primary Ciliary Dyskinesia ◽  
Central Pair ◽  
Pair Defect ◽  
Ciliary Dyskinesia

scholarly journals Pcdp1 is a central apparatus protein that binds Ca2+-calmodulin and regulates ciliary motility

2010 ◽  
Vol 189 (3) ◽  
pp. 601-612 ◽  
Author(s):  
Christen G. DiPetrillo ◽  
Elizabeth F. Smith
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Calcium Concentration ◽  
Beat Frequency ◽  
Calcium Sensor ◽  
Central Pair ◽  
Ciliary Motility ◽  
Significant Impairment ◽  
Central Apparatus ◽  
Cilia And Flagella ◽  
Ciliary Dyskinesia

For all motile eukaryotic cilia and flagella, beating is regulated by changes in intraciliary calcium concentration. Although the mechanism for calcium regulation is not understood, numerous studies have shown that calmodulin (CaM) is a key axonemal calcium sensor. Using anti-CaM antibodies and Chlamydomonas reinhardtii axonemal extracts, we precipitated a complex that includes four polypeptides and that specifically interacts with CaM in high [Ca2+]. One of the complex members, FAP221, is an orthologue of mammalian Pcdp1 (primary ciliary dyskinesia protein 1). Both FAP221 and mammalian Pcdp1 specifically bind CaM in high [Ca2+]. Reduced expression of Pcdp1 complex members in C. reinhardtii results in failure of the C1d central pair projection to assemble and significant impairment of motility including uncoordinated bends, severely reduced beat frequency, and altered waveforms. These combined results reveal that the central pair Pcdp1 (FAP221) complex is essential for control of ciliary motility.

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.

SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair–associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics

2020 ◽  
Vol 62 (3) ◽  
pp. 382-396 ◽  
Author(s):  
Sandra Cindrić ◽  
Gerard W. Dougherty ◽  
Heike Olbrich ◽  
Rim Hjeij ◽  
Niki Tomas Loges ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Central Pair ◽  
Ciliary Dyskinesia

scholarly journals Wdr47, Camsaps, and Katanin cooperate to generate ciliary central microtubules

2020 ◽  
Author(s):  
Hao Liu ◽  
Jianqun Zheng ◽  
Lei Zhu ◽  
Yawen Chen ◽  
Yirong Zhang ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Cooperative Work ◽  
Complete Loss ◽  
Ependymal Cells ◽  
Work Team ◽  
Central Pair ◽  
Central Lumen ◽  
Subcellular Compartments ◽  
Low Efficiency ◽  
Ciliary Dyskinesia

Abstract The axonemal central pair (CP) are non-centrosomal microtubules critical for planar ciliary beat. How they form, however, is poorly understood. Here, we show that mammalian CP formation requires cooperative activities of Katanin, Camsaps, and Wdr47. Katanin severs peripheral microtubules to produce central microtubule seeds in nascent cilia. Camsaps stabilize minus ends of the seeds to facilitate MT outgrowth, whereas Wdr47 concentrates Camsaps into the axonemal central lumen to properly position the central microtubules. Wdr47 deficiency in mouse multicilia results in complete loss of CP, rotatory beat, and primary ciliary dyskinesia. Overexpression of Camsaps induces central microtubules in Wdr47-/- ependymal cells but at the expense of low efficiency, abnormal numbers, and wrong location, whereas overexpression of a dominant inhibitor of Katanin impairs the CP formation. We propose that Wdr47, Camsaps, and Katanin constitute a general cooperative work team for the generation of non-centrosomal MT arrays in polarized subcellular compartments.

scholarly journals Wdr47, Camsaps, and Katanin cooperate to generate ciliary central microtubules

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hao Liu ◽  
Jianqun Zheng ◽  
Lei Zhu ◽  
Lele Xie ◽  
Yawen Chen ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Complete Loss ◽  
Ependymal Cells ◽  
Microtubule Binding ◽  
Central Pair ◽  
Microtubule Severing ◽  
Central Lumen ◽  
Subcellular Compartments ◽  
Low Efficiency ◽  
Ciliary Dyskinesia

AbstractThe axonemal central pair (CP) are non-centrosomal microtubules critical for planar ciliary beat. How they form, however, is poorly understood. Here, we show that mammalian CP formation requires Wdr47, Camsaps, and microtubule-severing activity of Katanin. Katanin severs peripheral microtubules to produce central microtubule seeds in nascent cilia. Camsaps stabilize minus ends of the seeds to facilitate microtubule outgrowth, whereas Wdr47 concentrates Camsaps into the axonemal central lumen to properly position central microtubules. Wdr47 deficiency in mouse multicilia results in complete loss of CP, rotatory beat, and primary ciliary dyskinesia. Overexpression of Camsaps or their microtubule-binding regions induces central microtubules in Wdr47−/− ependymal cells but at the expense of low efficiency, abnormal numbers, and wrong location. Katanin levels and activity also impact the central microtubule number. We propose that Wdr47, Camsaps, and Katanin function together for the generation of non-centrosomal microtubule arrays in polarized subcellular compartments.

Primary Ciliary Dyskinesia With Central Pair Agenesis

2012 ◽  
Vol 19 (6) ◽  
pp. 243-245
Author(s):  
Sikander Zulqarnain ◽  
Gene R. Pesola ◽  
Alain C. Borczuk ◽  
Jason A. Moche
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Central Pair ◽  
Ciliary Dyskinesia

scholarly journals Targeted NGS gene panel identifies mutations in RSPH1 causing primary ciliary dyskinesia and a common mechanism for ciliary central pair agenesis due to radial spoke defects

2014 ◽  
Vol 23 (13) ◽  
pp. 3362-3374 ◽  
Author(s):  
Alexandros Onoufriadis ◽  
Amelia Shoemark ◽  
Miriam Schmidts ◽  
Mitali Patel ◽  
Gina Jimenez ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Gene Panel ◽  
Common Mechanism ◽  
Central Pair ◽  
Radial Spoke ◽  
Targeted Ngs ◽  
Ciliary Dyskinesia
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