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A7805 - Mutations in C11ORF70 Cause Primary Ciliary Dyskinesia with Randomization of Left-Right Body Asymmetry Due to Outer and Inner Dynein Arm Defects
Author Block: H. Omran1, I. M. Höben1, R. Hjeij1, H. Olbrich1, G. W. Dougherty1, T. Menchen1, I. Aprea1, D. Frank1, P. Pennekamp1, B. Dworniczak1, J. Wallmeier1, J. Raidt1, K. G. Nielsen2, M. C. Philipsen3, F. Santamaria4, L. Venditto4, I. Amirav5, H. Mussaffi6, F. Prenzel7, K. Wu8, M. Schmidts8, N. T. Loges1; 1Department of General Pediatrics, University Hospital Muenster, Muenster, Germany, 2Pediatric Department, Pediatric Pulmonary Service, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 3Pediatric Department, Pediatric Pulmonary Service, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 4Department of Translational Medical Sciences, Univ of Naples, Napoli 80131, Italy, 5Pediatric, University of Alberta, Edmonton, AB, Canada, 6Pulmonary Institute, Schneider Children’s Medical Center of Israel and Sackler Faculty of Medicine, Tel Aviv, Israel, 7Clinic for Pediatrics and Adolescent Medicine, University Hospital Leipzig, Leipzig, Germany, 8Human Genetics Department, Radboud University Medical Center, Nijmegen, Netherlands.
RATIONALE: Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility and randomization of the left/right body axis caused by defects of motile cilia and sperm flagella. PCD diagnosis is difficult and relies on a combination of tests including nasal nitric oxide (nNO) production rate measurement, high-speed video microscopy analysis of cilia and ciliary structure analyses by transmission electron microscopy (TEM) and high-resolution immunofluorescence microscopy (IFM).
METHODS AND RESULTS: Using Whole Exome Sequencing we identified loss-of-function mutations in the chromosome 11 open reading frame C11ORF70 in PCD individuals from five distinct families. TEM analyses and high resolution IFM demonstrate that loss-of-function mutations in C11ORF70 cause immotility of respiratory cilia and sperm flagella, respectively, due to loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11ORF70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11ORF70 by RNA-Seq showed that C11ORF70 is expressed in ciliated respiratory cells and that the expression of C11ORF70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein arm assembly factors. Furthermore, using Yeast-2-hybrid assay we could show that C11ORF70 interacts with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11ORF70 is a novel preassembly factor involved in the pathogenesis of PCD.
CONCLUSION: Our results indicate that C11ORF70 is a component of the dynein arm cytoplasmic assembly machinery. Furthermore, loss of function of C11ORF70 causes PCD and male infertility. The identification of novel genetic defects that causes PCD and male infertility is of great clinical importance as well as for genetic counselling.