LETTER TO JMG Loci for primary ciliary dyskinesia map to chromosome 16p12.1-12.2 and 15q13.1-15.1 in Faroe Islands and Israeli Druze genetic isolates

P rimary ciliary dyskinesia (PCD; Immotile cilia syndrome; OMIM 242650) is an autosomal recessive disorder resulting from dysmotility of cilia and sperm flagella. Cilia and flagella function either to create circulation of fluid over a stationary cell surface or to propel a cell through fluid. 3 These related structures are highly complex organelles composed of over 200 different polypeptides. 5 The core or axoneme of cilia and flagella comprises a bundle of microtubules and many associated proteins. The microtubules are formed from a and b tubulin protofilaments and are arranged in a well recognised ‘9+2’ pattern: nine peripheral microtubule doublets in a ring connected around a central pair of microtubules by radial spoke proteins. The peripheral microtubules have dynein motor proteins attached and are connected with each other by nexin links. In human beings, ciliated epithelium can be found lining the respiratory tract, including the sinuses and middle ear, the brain ependyma, the female oviduct, and the male vas deferens. Cilia in the respiratory tract play an important part in airway clearance of respiratory secretions. In primary ciliary dyskinesia, impaired mucociliary clearance causes recurrent respiratory tract infections including chronic otitis media, rhinitis, and sinusitus, often leading to permanent lung damage (bronchiectasis). Patients are also often subfertile due to sperm tail immotility and immotile oviduct cilia. About half of the patients have defects of laterality, usually complete mirror-image reversal of the left-right axis (situs inversus) and this association is known as Kartagener syndrome (OMIM 244400). The defects in left-right axis determination associated with primary ciliary dyskinesia are proposed to result from dysfunction of the embryonic node monocilia during development. Primary ciliary dyskinesia has an incidence of 1 in 20 000 with enrichment in certain populations. 13 Diagnosis is made on brushings or biopsy of nasal epithelium by demonstration of abnormal ciliary beating, and by demonstration of ultrastructural defects of cilia by electron microscopy. 15 Primary ciliary dyskinesia is a chronic condition with symptoms present from birth but there is significant variation both in clinical severity and the age at which the condition is diagnosed. 15 16 There is usually a progressively greater impact on health from the second decade onwards, producing significant morbidity and life style restriction. In some cases of severe lung damage, heart-lung transplantation is required and in general patients greatly benefit from early diagnosis and management. 19 Primary ciliary dyskinesia is a phenotypically heterogeneous condition associated with a variety of ultrastructural abnormalities of the cilia and sperm flagella. These include absent dynein arms (approximately 70–80% of cases), absent radial spokes (5–10%), absent central pair microtubules, other rarer microtubular defects, and random ciliary orientation. Genetic linkage analysis and mutational studies in patients with primary ciliary dyskinesia have shown that this disease is genetically heterogeneous, even within groups of families with the same specific ultrastructural defect. An unusual probable dominant inheritance pattern has also been reported for the disease. Mutations in genes encoding two different axonemal outer dynein arm components (DNAI1 and DNAH5) have been shown to cause primary ciliary dyskinesia in a number of patients with outer dynein arm defects. 29 Defects in another dynein, DNAH11, have been