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May 2011 - present
January 2010 - April 2011
March 2009 - December 2009
Publications
Publications (75)
Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder affecting the function of motile cilia in several organ systems. In PCD, male infertility is caused by defective sperm flagella composition or deficient motile cilia function in the efferent ducts of the male reproductive system. Different PCD-associated genes encoding axonemal components...
Purpose:
Primary ciliary dyskinesia (PCD) is a heterogeneous disorder including respiratory symptoms, laterality defects and infertility caused by dysfunction of motile cilia. Most PCD-causing variants result in abnormal outer dynein arms (ODAs), which provide the generative force for respiratory ciliary beating and proper mucociliary clearance....
TP73 belongs to the TP53 family of transcription factors and has therefore been well studied in cancer research. Studies in mice, however, have revealed non-oncogenic activities related to multiciliogenesis. Utilizing whole-exome sequencing analysis in a cohort of individuals with a mucociliary clearance disorder and cortical malformation, we ident...
Motile cilia line the efferent ducts of the mammalian male reproductive tract. Several recent mouse studies have demonstrated that a reduced generation of multiple motile cilia in efferent ducts is associated with obstructive oligozoospermia and fertility issues. However, the sole impact of efferent duct cilia dysmotility on male infertility has no...
Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that pre...
Oral-Facial-Digital type I (OFD1) is a rare inherited form of renal cystic disease associated with ciliary dysfunction. This disorder is due to mutations in the OFD1 gene that encodes a protein localized to centrosomes and basal bodies in different cell types. Immunofluorescence analysis demonstrated that OFD1 displays a dynamic distribution during...
Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane condu...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Background
Nearly one in 100 live births presents with congenital heart defects (CHD). CHD is frequently associated with laterality defects, such as situs inversus , a mirrored positioning of internal organs. Body laterality is established by a complex process: monocilia at the embryonic left-right organizer facilitate both the generation and sensi...
Background:
Lower respiratory tract infections (LRIs) are a major cause of hospitalization for children and adolescents with a tracheostomy. The aim of this study was to identify risk factors for LRI.
Methods:
In this retrospective study, we assessed the number of LRI and hospitalizations for LRI from 2004 to 2014 at the University Hospital Muen...
Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which p...
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal NO measurement, analysis of ciliary beating, transmission electron microscopy (TEM) and/or genetic testing. In most genetic PCD variants laterality defects can occur. However, PCD individuals with central pair...
The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcrip...
Background:
Cough is a key symptom in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD).
Objective:
The study objectives were to test whether cough is related to parameters reflecting their disease severity and whether CF and PCD differ in cough frequency.
Methods:
In this prospective observational study, we used a microp...
The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four con...
ODA-DC associated protein ARMC4 localizes normally in MNS1-deficient cilia but fails to assemble in the distal axonemes in respiratory epithelial cells with a double deficiency of MNS1 and DNAH5.
(PDF)
List of homozygous variants after filtering in individual MS-II-1.
(PDF)
DNAH5 localizes normally to the axonemes with MNS1 deficiency.
(PDF)
Linkage analysis in individual OI-11 II6.
(PDF)
Filtering process for gene variants identified through whole exome sequencing.
(PDF)
MNS1 mutations do not result in additional structural defects.
(PDF)
List of homozygous variants after filtering in individual AL-IV-3.
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List of homozygous variants after filtering in individual BG-II-1.
(PDF)
Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11ORF70 in PCD individuals from five distinct families. Transmission electron micr...
Cilia are organelles specialized for movement and signaling. To infer when during evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from sea urchins, sea anemones, and choanoflagellates. We identified 437 high-confidence ciliary candidate proteins conserved in mammals and discovered that Hedgehog and...
Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility and randomization of the left/right body axis caused by defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open reading frame C11ORF70 in PCD individuals from five distinct families. Transmission electron microscopy...
Background: Bloodstream pathogens can be identified by multiplex PCR (SeptiFast (SF)) or blood culture (BC); whether these pathogens are present in cystic fibrosis (CF) patients during febrile pulmonary exacerbations (FPE) has not been sufficiently studied.
Cilia are organelles specialized for movement and signaling. To infer when during animal evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from three organisms: sea urchins, sea anemones and choanoflagellates. From these ciliomes, we identified 437 high confidence ciliary candidate proteins conserved...
Primary ciliary dyskinesia (PCD) is a genetic condition of impaired ciliary beating, characterized by chronic infections of the upper and lower airways and progressive lung failure. Defects of the outer dynein arms are the most common cause of PCD. In about half of the affected individuals, PCD occurs with situs inversus (Kartagener syndrome). A mi...
The cilium is an essential organelle at the surface of most mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, tran...
Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of...
Introduction Primary Ciliary Dyskiensia (PCD) describes a clinically and genetically heterogeneous group of hereditary disorders characterized by chronic mucopurulent infections of the airways caused by dysfunction of multiple motile cilia. Mutations in > 30 genes have been described to cause PCD. We present a new genetic PCD-variant caused by defe...
Multiprotein complexes referred to as outer dynein arms (ODAs) develop the main mechanical force to generate the ciliary and flagellar beat. ODA defects are the most common cause of primary ciliary dyskinesia (PCD), a congenital disorder of ciliary beating, characterized by recurrent infections of the upper and lower airways, as well as by progress...
Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interacti...
Rationale:
Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorder due to impaired mucociliary clearance. Conventional transmission electron microscopy is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in about 30% of PCD cases, which have norm...
Reduced generation of multiple motile cilia (RGMC) is a novel chronic destructive airway disease within the group of mucociliary clearance disorders with only few cases reported. Mutations in two genes, CCNO and MCIDAS, have been identified as a cause of this disease, both leading to a greatly reduced number of cilia and causing impaired mucociliar...
Multiciliated epithelial cells protect the upper and lower airways from chronic bacterial infections by moving mucus and debris outward. Congenital disorders of ciliary beating, referred to as primary ciliary dyskinesia (PCD), are characterized by deficient mucociliary clearance and severe, recurrent respiratory infections. Numerous genetic defects...
Study question:
What is the motor protein composition and function of human fallopian tube (FT) cilia?
Summary answer:
Although the motor protein composition and function of human FT cilia resemble that of respiratory cilia, females with primary ciliary dyskinesia (PCD) are not necessarily infertile.
What is known already:
FTs are lined with m...
Introduction: Primary Ciliary Dyskinesia (PCD) is a rare, genetically heterogenous disorder leading to recurrent respiratory tract infections due to abnormal ciliary motility causing impaired mucociliary clearance. High-speed videomicroscopy analysis (HVMA) of ciliary beat pattern (CBP) and frequency as the current first-line diagnostic tool is an...
We present a stratification of the genetic basis of primary ciliary dyskinesia (PCD), based on screening >230 individuals for gene mutations using various approaches including whole exome sequencing. PCD is a genetically heterogeneous recessive ciliopathy, characterized by chronic lung disease and laterality and fertility defects arising from cilia...
A diverse family of cytoskeletal dynein motors powers various cellular transport systems, including axonemal dyneins generating the force for ciliary and flagellar beating essential to movement of extracellular fluids and of cells through fluid. Multisubunit outer dynein arm (ODA) motor complexes, produced and preassembled in the cytosol, are trans...
Primary ciliary dyskinesia (PCD) is a rare genetic disorder leading to recurrent respiratory tract infections. High-speed video-microscopy analysis (HVMA) of ciliary beating, currently the first-line diagnostic tool for PCD in most centres, is challenging because recent studies have expanded the spectrum of HVMA findings in PCD from grossly abnorma...
Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder. Affected persons suffer from recurrent infections of upper and lower airways because of highly reduced numbers of multiple motile respiratory cilia. Here we report recessive loss-of-function and missense mutations in MCIDAS-encoding Multicilin, which was sh...
Using a whole-exome sequencing strategy, we identified recessive CCNO (encoding cyclin O) mutations in 16 individuals suffering from chronic destructive lung disease due to insufficient airway clearance. Respiratory epithelial cells showed a marked reduction in the number of multiple motile cilia (MMC) covering the cell surface. The few residual ci...
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed ex...
Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show tha...
DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2-4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed indepe...
The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which are preassembled in the cytoplasm prior to transport to the ciliary axonemal compartment. In humans, defects in structural components, docking complexes, or cytoplasmic assembly factors can cause primary ciliary dyskin...
Two proteins implicated in inherited deafness, myosin IIIa, a plus-end-directed motor, and espin, an actin-bundling protein containing the actin-monomer-binding motif WH2, have been shown to influence the length of mechanosensory stereocilia. Here we report that espin 1, an ankyrin repeat-containing isoform of espin, colocalizes with myosin IIIa at...
Figure S3
Actin-activated ATPase activity of myosin IIIa 2IQ constructs. a) A diagram of the myosin IIIa 2IQ constructs examined. b) The results for myosin IIIa 2IQ K50R (squares) are compared to that of myosin IIIa 2IQ wild-type 37 (open circles) and myosin IIIa 2IQ DKinase28 (diamonds). The steady-state ATPase rate of 0.1 mM myosin was measured u...
Figure S4
The first 24 amino acids of the 3THDI domain are sufficient for binding espin 1. (a) The mapping of the GFP-3THDI Δ33 fusion protein is illustrated. (b) GFP-3THDI Δ33 (green) colocalizes with espin 1 (red, labeled with PB539). PB539 (red) is labeled with Alexa Fluor 568-conjugated secondary antibody. Scale bar is 5 µm. (c) GST pull-down s...
Figure S2
Schematic map of wild-type and deletion constructs. Only the myosin IIIa coding regions are shown. Full-length espin 1 is 871 amino acid-long in mouse and 854 amino acid-long in human (mouse espin 1 is illustrated here). The tail domain of myoIIIa encompasses 3THDI, 3THDII, and the third IQ domain, however; only 3THDI and 3THDII were cons...
Figure S5
Co-localization of myosin IIIa and espin 1 at filopodia tips. (a) Close up views of COS-7 cells show that espin 1 (red) colocalizes with GFP-myoIIIa ΔK (green) at the filopodia tips when these two proteins are coexpressed in COS-7 cells. (b) Espin 1 (red) colocalizes with GFP-myoIIIa ΔK (green) at the filopodia tips (actin is labeled Alex...
Figure S1
Specificity of the antibodies generated against the ARD of espin 1. (a) Immunoblots of lysates from COS-7 cells transfected with GFP-espin 1, GFP-ARD, and GFP-myoIIIa ΔK as well as lysates from bacteria expressing GST-ARD show that both PB538 and PB539 specifically recognize the ARD of espin 1. (b) GFP-espin 1 (left column) overexpressed...
The link between Ras transformation and enhanced cell migration due to altered integrin signaling is well established in tumorigenesis, however there remain gaps in our understanding of its mechanism. The Ras suppressor, Rsu-1, has recently been linked to the IPP (integrin-linked kinase {ILK}, PINCH-1/LIMS1, parvin) focal adhesion complex based on...
In the Addendum on page 154 and in the article's reference section, the reference, Chan et al., 2005 was omitted. The sentence in the Addendum should have read:
After submission of this manuscript, a report [Chan et al., 2005] described a gene sequence named Spef1 that is identical to CLAMP and is localized to mouse sperm flagella.
The full referen...
Rsu-1 is a highly conserved leucine rich repeat (LRR) protein that is expressed ubiquitously in mammalian cells. Rsu-1 was identified based on its ability to inhibit transformation by Ras, and previous studies demonstrated that ectopic expression of Rsu-1 inhibited anchorage-independent growth of Ras-transformed cells and human tumor cell lines. Us...
Hair cells are specialized mechanoreceptors common to auditory and vestibular sensory organs of mammalian and non-mammalian species. Different hair cells are believed to share common features related to their mechanosensory function. It has been shown that hair cells possess various forms of motile properties that enhance their receptor function. M...
Previous studies demonstrated that the Ras suppressor, RSU-1, localizes to human chromosome 10p13, a region frequently deleted in high grade gliomas, and that RSU-1 expression inhibited the tumorigenesis of a glioblastoma cell line. We have now examined RNA from human glial tumors for RSU-1 expression by RT-PCR using primers for the 5' and 3' ends...
Signal transduction from tyrosine kinase receptors mediates growth regulation of breast cancer cells in part through the GTPase Ras and downstream kinases. Rsu-1 is a cDNA previously identified as an inhibitor of Ras-induced transformation. An HA-epitope tagged Rsu-1 cDNA was introduced into the MCF7 breast carcinoma cell line. Stable transfectants...
Typescript (Photocopy). Thesis (Ph. D.)--Uniformed Services University of the Health Sciences, 2000.
