RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa

• Published in: Journal of medical genetics Vol. 43; no. 4; pp. 326 - 333
• Main Authors: Moore, A, Escudier, E, Roger, G, Tamalet, A, Pelosse, B, Marlin, S, Clément, A, Geremek, M, Delaisi, B, Bridoux, A-M, Coste, A, Witt, M, Duriez, B, Amselem, S
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-04-2006; BMJ; BMJ Publishing Group LTD; BMJ Publishing Group; BMJ Group
• Subjects: Adolescent; Adult; Biological and medical sciences; Cardiology. Vascular system; Cilia; Cilia - physiology; Cilia - ultrastructure; DNA Mutational Analysis; Dyskinesia; Eye Proteins; Eye Proteins - genetics; Families & family life; Female; General aspects. Genetic counseling; Genes; Genetic Diseases, X-Linked; Genetic Diseases, X-Linked - diagnosis; Genetic Diseases, X-Linked - genetics; Genetics; Genotype; Genotype & phenotype; Human genetics; Human health and pathology; Humans; IFT; intraflagellar transport; Kartagener Syndrome; Kartagener Syndrome - complications; Kartagener Syndrome - diagnosis; Kartagener Syndrome - genetics; Life Sciences; Male; Medical genetics; Medical sciences; Microsatellite Repeats; Mutation; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; ODA; Original; outer dynein arms; Patients; PCD; Pedigree; Phenotype; primary ciliary dyskinesia; PTA; Pulmonology and respiratory tract; pure tone audiometry; Respiratory Mucosa; Respiratory Mucosa - ultrastructure; Retinitis Pigmentosa; Retinitis Pigmentosa - complications; Retinitis Pigmentosa - diagnosis; Retinitis Pigmentosa - genetics; RPGR; Sensory Organs; Sinusitis; Thoracic surgery; X linked primary ciliary dyskinesia; X linked retinitis pigmentosa; XLRP; Human; Sex linked character; Nervous system diseases; Retinopathy; Retinitis pigmentosa; Patient; Complexes; Cerebral disorder; Involuntary movement; Genetic disease; Eye disease; Phenotype; Central nervous system disease; Genetics; X-Chromosome; Neurological disorder; Extrapyramidal syndrome; Dyskinesia
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2005.034868

Introduction: Primary ciliary dyskinesia (PCD) is a rare disease classically transmitted as an autosomal recessive trait and characterised by recurrent airway infections due to abnormal ciliary structure and function. To date, only two autosomal genes, DNAI1 and DNAH5 encoding axonemal dynein chains, have been shown to cause PCD with defective outer dynein arms. Here, we investigated one non-consanguineous family in which a woman with retinitis pigmentosa (RP) gave birth to two boys with a complex phenotype combining PCD, discovered in early childhood and characterised by partial dynein arm defects, and RP that occurred secondarily. The family history prompted us to search for an X linked gene that could account for both conditions. Results: We found perfect segregation of the disease phenotype with RP3 associated markers (Xp21.1). Analysis of the retinitis pigmentosa GTPase regulator gene (RPGR) located at this locus revealed a mutation (631_IVS6+9del) in the two boys and their mother. As shown by study of RPGR transcripts expressed in nasal epithelial cells, this intragenic deletion, which leads to activation of a cryptic donor splice site, predicts a severely truncated protein. Conclusion: These data provide the first clear demonstration of X linked transmission of PCD. This unusual mode of inheritance of PCD in patients with particular phenotypic features (that is, partial dynein arm defects and association with RP), which should modify the current management of families affected by PCD or RP, unveils the importance of RPGR in the proper development of both respiratory ciliary structures and connecting cilia of photoreceptors.