Antony, D, Becker-Heck, A, Zariwala, MA, Schmidts, M, Onoufriadis, A, Forouhan, M, Wilson, R, Taylor-Cox, T, Dewar, A, Jackson, C, Goggin, P, Loges, NT, Olbrich, H, Jaspers, M, Jorissen, M, Leigh, MW, Wolf, WE, Daniels, MLA, Noone, PG, Ferkol, TW, Sagel, SD, Rosenfeld, M, Rutman, A, Dixit, A, O'Callaghan, C, Lucas, JS, Hogg, C, Scambler, PJ, Emes, RD, Chung, EMK, Shoemark, A, Knowles, MR, Omran, H and Mitchison, HM (2013) Mutations in CCDC39 and CCDC40 are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms. Human Mutation. pp. 462-472.

Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed 'radial spoke defect.' We sequenced CCDC39 and CCDC40 in 54 'radial spoke defect' families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice, and frameshift predicting early protein truncation, which suggests this defect is caused by 'null' alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganization and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as 'IDA and microtubular disorganisation defect,' rather than 'radial spoke defect'. 2012 Wiley Periodicals, Inc

Item Type:	Article
Additional Information:	pubid: 154 nvp_institute: NIBR contributor_address: (Antony, Schmidts, Onoufriadis, Forouhan, Scambler, Mitchison) Molecular Medicine Unit and Birth Defects Research Centre, University College London (UCL), Institute of Child Health, London, United Kingdom (Becker-Heck, Loges, Olbrich, Omran) Department of Pediatrics and Adolescent Medicine, University Hospital Muenster, Muenster, Germany (Zariwala) Department of Pathology and Laboratory Medicine, UNC School of Medicine, Chapel Hill, NC, United States (Wilson) Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London, United Kingdom (Taylor-Cox, Dewar, Hogg, Shoemark) Department of Paediatric Respiratory Medicine, Electron Microscopy Unit, Royal Brompton and Harefield NHS Trust, London, United Kingdom (Jackson, Goggin, Lucas) Primary Ciliary Dyskinesia Group, University of Southampton Faculty of Medicine, Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton, United Kingdom (Jaspers, Jorissen) University Hospitals Leuven, Department of Otorhinolaryngology, Leuven, Belgium (Leigh) Department of Pediatrics, UNC School of Medicine, Chapel Hill, NC, United States (Wolf, Daniels, Noone, Knowles) Department of Medicine, UNC School of Medicine, Chapel Hill, NC, United States (Ferkol) Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States (Sagel) Department of Pediatrics, University of Colorado, School of Medicine, Aurora, CO, United States (Rosenfeld) Children's Hospital, Regional Medical Center, Seattle, WA, United States (Rutman, O'Callaghan) Department of Infection, Immunity and Inflammation, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom (Dixit) Department of Clinical Genetics, Nottingham City Hospital, Nottingham, United Kingdom (Emes) School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom (Chung) General and Adolescent Paediatric Unit, University College London (UCL), Institute of Child Health, London, United Kingdom (Antony) Dasman Genome Center Unit, P.O.Box 1180, Dasman 15462, Kuwait (Becker-Heck) Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus Basel, Basel, CH-4056, Switzerland
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/21986