title: Systematic Analysis of CCNO Variants in a Defined Population: Implications for Clinical Phenotype and Differential Diagnosis.
abstract: 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 mucociliary clearance. This study was designed to identify the prevalence of CCNO mutations in Israel and further delineate the clinical characteristics of RGMC. We analyzed 170 families with mucociliary clearance disorders originating from Israel for mutations in CCNO and identified two novel mutations (c.165delC, p.Gly56Alafs*38; c.638T>C, p.Leu213Pro) and two known mutations in 15 individuals from 10 families (6% prevalence). Pathogenicity of the missense mutation (c.638T>C, p.Leu213Pro) was demonstrated by functional analyses in Xenopus. Combining these 15 patients with the previously reported CCNO case reports revealed rapid deterioration in lung function, an increased prevalence of hydrocephalus (10%) as well as increased female infertility (22%). Consistent with these findings, we demonstrate that CCNO expression is present in murine ependyma and fallopian tubes. CCNO is mutated more frequently than expected from the rare previous clinical case reports, leads to severe clinical manifestations, and should therefore be considered an important differential diagnosis of mucociliary clearance disorders.
authors.affiliation: Ziv Medical Center, Faculty of Medicine, Bar IIan University, Safed 13100, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Amirav
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Wallmeier
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
authors.forename: Tabea
authors.initials: T
authors.lastname: Menchen
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Pennekamp
authors.affiliation: Pulmonary Institute, Schneider Children's Medical Center of Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Huda
authors.initials: H
authors.lastname: Mussaffi
authors.affiliation: Ziv Medical Center, Faculty of Medicine, Bar IIan University, Safed 13100, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Abitbul
authors.affiliation: Institute of Pulmonology, Hadassah-Hebrew University Medical Centers, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Avital
authors.affiliation: Rambam Medical Center, Haifa, Israel.
authors.forename: Lea
authors.initials: L
authors.lastname: Bentur
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: Dougherty
authors.affiliation: Saint Vincent De-Paul Hospital, Nazareth, Israel.
authors.forename: Elias
authors.initials: E
authors.lastname: Nael
authors.affiliation: Edmond & Lili Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Lavie
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, San Diego, California, 92186.
authors.forename: Chris
authors.initials: C
authors.lastname: Kintner
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D000818:Animals; D002925:Ciliary Motility Disorders / Q000175:diagnosis* / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D056426:Genetic Loci; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D021381:Protein Transport; D013902:Radiography, Thoracic; D012129:Respiratory Function Tests; D014057:Tomography, X-Ray Computed; D014982:Xenopus laevis
chemical_list: C492570:CCNO protein, human; D045647:DNA Glycosylases
keywords: CCNO; PCD; RGMC; mucociliary clearance disorder; primary ciliary dyskinesia