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

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


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.

Keywords: CCNO; PCD; RGMC; mucociliary clearance disorder; primary ciliary dyskinesia.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ciliary Motility Disorders / diagnosis*
  • Ciliary Motility Disorders / genetics*
  • DNA Glycosylases / genetics*
  • DNA Glycosylases / metabolism
  • DNA Mutational Analysis
  • Diagnosis, Differential
  • Female
  • Frameshift Mutation
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Testing
  • Genetic Variation*
  • Humans
  • Male
  • Mice
  • Mutation
  • Mutation, Missense
  • Phenotype
  • Protein Transport
  • Radiography, Thoracic
  • Respiratory Function Tests
  • Tomography, X-Ray Computed
  • Xenopus laevis


  • CCNO protein, human
  • DNA Glycosylases