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Hum Mutat. 2016 Apr;37(4):396-405. doi: 10.1002/humu.22957. Epub 2016 Feb 4.

Systematic Analysis of CCNO Variants in a Defined Population: Implications for Clinical Phenotype and Differential Diagnosis.

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Ziv Medical Center, Faculty of Medicine, Bar IIan University, Safed 13100, Israel.
Department of General Pediatrics, University Children's Hospital Muenster, Muenster, 48149, Germany.
Pulmonary Institute, Schneider Children's Medical Center of Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Institute of Pulmonology, Hadassah-Hebrew University Medical Centers, Jerusalem, Israel.
Rambam Medical Center, Haifa, Israel.
Saint Vincent De-Paul Hospital, Nazareth, Israel.
Edmond & Lili Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, San Diego, California, 92186.


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.


CCNO; PCD; RGMC; mucociliary clearance disorder; primary ciliary dyskinesia

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