Primary ciliary dyskinesia (PCD) is a genetically heterogeneous inherited disorder arising from dysmotility of motile cilia and sperm. This is associated with a variety of ultrastructural defects of the cilia and sperm axoneme that affect movement, leading to clinical consequences on respiratory-tract mucociliary clearance and lung function, fertility, and left-right body-axis determination. We performed whole-genome SNP-based linkage analysis in seven consanguineous families with PCD and central-microtubular-pair abnormalities. This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0). Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1. Haplotype analysis identified a common ancestral founder effect RSPH4A mutation present in UK-Pakistani pedigrees. Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head. In situ hybridization of murine Rsph9 shows gene expression restricted to regions containing motile cilia. Investigation of the effect of knockdown or mutations of RSPH9 orthologs in zebrafish and Chlamydomonas indicate that radial spoke head proteins are important in maintaining normal movement in motile, "9+2"-structure cilia and flagella. This effect is rescued by reintroduction of gene expression for restoration of a normal beat pattern in zebrafish. Disturbance in function of these genes was not associated with defects in left-right axis determination in humans or zebrafish.
Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation, and to establish laterality1. Cilia motility defects cause Primary Ciliary Dyskinesia (PCD, MIM 242650), a disorder affecting 1:15-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive cilia bending2. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD linked loci3. Here we show that the zebrafish cilia paralysis mutant schmalhanstn222 (smh) mutant encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a regulated gene. Screening 146 unrelated PCD families identified patients in six families with reduced outer dynein arms, carrying mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103 functions as a tightly bound, axoneme-associated protein. The results identify Ccdc103 as a novel dynein arm attachment factor that when mutated causes Primary Ciliary Dyskinesia.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by chronic destructive airway disease and randomization of left/right body asymmetry. Males often have reduced fertility due to impaired sperm tail function. The complex PCD phenotype results from dysfunction of cilia of the airways and the embryonic node and the structurally related motile sperm flagella. This is associated with underlying ultrastructural defects that frequently involve the outer dynein arm (ODA) complexes that generate cilia and flagella movement. Applying a positional and functional candidate-gene approach, we identified homozygous loss-of-function DNAI2 mutations (IVS11+1G> A) in four individuals from a family with PCD and ODA defects. Further mutational screening of 105 unrelated PCD families detected two distinct homozygous mutations, including a nonsense (c.787C > T) and a splicing mutation (IVS3-3T > G) resulting in out-of-frame transcripts. Analysis of protein expression of the ODA intermediate chain DNAI2 showed sublocalization throughout respiratory cilia. Electron microscopy showed that mutant respiratory cells from these patients lacked DNAI2 protein expression and exhibited ODA defects. High-resolution immunofluorescence imaging demonstrated absence of the ODA heavy chains DNAH5 and DNAH9 from all DNAI2 mutant ciliary axonemes. In addition, we demonstrated complete or distal absence of DNAI2 from ciliary axonemes in respiratory cells of patients with mutations in genes encoding the ODA chains DNAH5 and DNAI1, respectively. Thus, DNAI2 and DNAH5 mutations affect assembly of proximal and distal ODA complexes, whereas DNAI1 mutations mainly disrupt assembly of proximal ODA complexes.
Rationale: Primary ciliary dyskinesia (PCD) is a rare, usually autosomal recessive, genetic disorder characterized by ciliary dysfunction, sino-pulmonary disease, and situs inversus. Disease-causing mutations have been reported in DNAI1 and DNAH5 encoding outer dynein arm (ODA) proteins of cilia. Objectives: We analyzed DNAI1 to identify disease-causing mutations in PCD and to determine if the previously reported IVS1؉2_3insT (219؉3insT) mutation represents a "founder" or "hot spot" mutation. Methods: Patients with PCD from 179 unrelated families were studied. Exclusion mapping showed no linkage to DNAI1 for 13 families; the entire coding region was sequenced in a patient from the remaining 166 families. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on nasal epithelial RNA in 14 families. Results: Mutations in DNAI1 including 12 novel mutations were identified in 16 of 179 (9%) families; 14 harbored biallelic mutations. Deep intronic splice mutations were not identified by reverse transcriptase-polymerase chain reaction. The prevalence of mutations in families with defined ODA defect was 13%; no mutations were found in patients without a defined ODA defect. The previously reported IVS1؉2_3insT mutation accounted for 57% (17/30) of mutant alleles, and marker analysis indicates a common founder for this mutation. Seven mutations occurred in three exons (13, 16, and 17); taken together with previous reports, these three exons are emerging as mutation clusters harboring 29% (12/42) of mutant alleles. Conclusions: A total of 10% of patients with PCD are estimated to harbor mutations in DNAI1; most occur as a common founder IVS1؉2_3insT or in exons 13, 16, and 17. This information is useful for establishing a clinical molecular genetic test for PCD.
Table 1 Advantages and disadvantages of walkie talkie use in health care settings Advantages Disadvantages Low cost Non-secure channel Easy to decontaminate per IPC guidance Miscommunication between multiple teams sharing the same channel Simple to operate Radio frequencies may be obstructed by hospital structures (e.g. lead lining within radiotherapy departments) Can be used while wearing PPE Specific communication approach required Does not rely on telecommunication infrastructure "One to many" communication provides instant access to the whole team
Table of contentsWORKSHOP 4: Challenging clinical scenarios (CS01–CS06)CS01 Bullous lesions in two children: solitary mastocytomaS. Tolga Yavuz, Ozan Koc, Ali Gungor, Faysal GokCS02 Multi-System Allergy (MSA) of cystic fibrosis: our institutional experienceJessica Hawley, Christopher O’Brien, Matthew Thomas, Malcolm Brodlie, Louise MichaelisCS03 Cold urticaria in pediatric age: an invisible cause for severe reactionsInês Mota, Ângela Gaspar, Susana Piedade, Graça Sampaio, José Geraldo Dias, Miguel Paiva, Mário Morais-AlmeidaCS04 Angioedema with C1 inhibitor deficiency in a girl: a challenge diagnosisCristina Madureira, Tânia Lopes, Susana Lopes, Filipa Almeida, Alexandra Sequeira, Fernanda Carvalho, José OliveiraCS05 A child with unusual multiple organ allergy disease: what is the primer?Fabienne Gay-CrosierCS06 A case of uncontrolled asthma in a 6-year-old patientIoana-Valentina Nenciu, Andreia Florina Nita, Alexandru Ulmeanu, Dumitru Oraseanu, Carmen ZapucioiuORAL ABSTRACT SESSION 1: Food allergy (OP01–OP06)OP01 Food protein-induced enterocolitis syndrome: oral food challenge outcomes for tolerance evaluation in a Pediatric HospitalAdrianna Machinena, Olga Domínguez Sánchez, Montserrat Alvaro Lozano, Rosa Jimenez Feijoo, Jaime Lozano Blasco, Mònica Piquer Gibert, Mª Teresa Giner Muñoz, Marcia Dias da Costa, Ana Maria Plaza MartínOP02 Characteristics of infants with food protein-induced enterocolitis syndrome and allergic proctocolitisEbru Arik Yilmaz, Özlem Cavkaytar, Betul Buyuktiryaki, Ozge Soyer, Cansin SackesenOP03 The clinical and immunological outcomes after consumption of baked egg by 1–5 year old egg allergic children: results of a randomised controlled trialMerrynNetting, Adaweyah El-Merhibi, Michael Gold, PatrickQuinn, IrmeliPenttila, Maria MakridesOP04 Oral immunotherapy for treatment of egg allergy using low allergenic, hydrolysed eggStavroula Giavi, Antonella Muraro, Roger Lauener, Annick Mercenier, Eugen Bersuch, Isabella M. Montagner, Maria Passioti, Nicolò Celegato, Selina Summermatter, Sophie Nutten, Tristan Bourdeau, Yvonne M. Vissers, Nikolaos G. PapadopoulosOP05 Chemical modification of a peanut extract results in an increased safety profile while maintaining efficacyHanneke van der Kleij, Hans Warmenhoven, Ronald van Ree, Raymond Pieters, Dirk Jan Opstelten, Hans van Schijndel, Joost SmitOP06 Administration of the yellow fever vaccine in egg allergic childrenRoisin Fitzsimons, Victoria Timms, George Du ToitORAL ABSTRACT SESSION 2: Asthma (OP07–OP12)OP07 Previous exacerbation is the most important risk factor for future exacerbations in school-age children with asthmaS. Tolga Yavuz, Guven Kaya, Mustafa Gulec, Mehmet Saldir, Osman Sener, Faysal GokOP08 Comparative study of degree of severity and laboratory changes between asthmatic children using different acupuncture modalitiesNagwa Hassan, Hala Shaaban, Hazem El-Hariri, Ahmed Kamel Inas E. MahfouzOP09 The concentration of exhaled carbon monoxide in asthmatic children with different controlled stadiumPapp Gabor, Biro Gabor, Kovacs CsabaOP10 ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.