TY - JOUR
T1 - Systematic Analysis of CCNO Variants in a Defined Population
T2 - Implications for Clinical Phenotype and Differential Diagnosis
AU - and for the Israeli PCD Consortium Investigators
AU - Amirav, Israel
AU - Wallmeier, Julia
AU - Loges, Niki T.
AU - Menchen, Tabea
AU - Pennekamp, Petra
AU - Mussaffi, Huda
AU - Abitbul, Revital
AU - Avital, Avraham
AU - Bentur, Lea
AU - Dougherty, Gerard W.
AU - Nael, Elias
AU - Lavie, Moran
AU - Olbrich, Heike
AU - Werner, Claudius
AU - Kintner, Chris
AU - Omran, Heymut
AU - Alkrinawi, Soliman
AU - Aviram, Micha
AU - Rotschild, Moshe
AU - Blau, Hannah
AU - Kerem, Eytan
AU - Cohen-Cymberknoh, Malena
AU - Shoseyov, David
AU - Springer, Chaim
AU - Hevroni, Avigdor
AU - Dabbah, Husein
AU - Elizur, Arnon
AU - Picard, Elie
AU - Goldberg, Shmuel
AU - Efrati, Ori
AU - Yahav, Yakov
AU - Luder, Anthony
AU - Rivlin, Joseph
AU - Livnat, Galit
AU - Roth, Yehudah
AU - Mandelberg, Avigdor
AU - Sivan, Yakov
AU - Soferman, Ruth
N1 - Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
KW - CCNO
KW - Mucociliary clearance disorder
KW - PCD
KW - Primary ciliary dyskinesia
KW - RGMC
UR - http://www.scopus.com/inward/record.url?scp=84960487751&partnerID=8YFLogxK
U2 - 10.1002/humu.22957
DO - 10.1002/humu.22957
M3 - Article
C2 - 26777464
AN - SCOPUS:84960487751
SN - 1059-7794
VL - 37
SP - 396
EP - 405
JO - Human Mutation
JF - Human Mutation
IS - 4
ER -