Primary ciliary dyskinesia (PCD; MIM 242650) is an autosomal recessive disorder of ciliary dysfunction with extensive genetic heterogeneity. PCD is characterized by bronchiectasis and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome). We characterized the transcript and the genomic organization of the axonemal heavy chain dynein type 11 (DNAH11) gene, the human homologue of murine Dnah11 or lrd, which is mutated in the iv͞iv mouse model with situs inversus. To assess the role of DNAH11, which maps on chromosome 7p21, we searched for mutations in the 82 exons of this gene in a patient with situs inversus totalis, and probable Kartagener syndrome associated with paternal uniparental disomy of chromosome 7 (patUPD7). We identified a homozygous nonsense mutation (R2852X) in the DNAH11 gene. This patient is remarkable because he is also homozygous for the F508del allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sequence analysis of the DNAH11 gene in an additional 6 selected PCD sibships that shared DNAH11 alleles revealed polymorphic variants and an R3004Q substitution in a conserved position that might be pathogenic. We conclude that mutations in the coding region of DNAH11 account for situs inversus totalis and probably a minority of cases of PCD.

Obstructive sleep apnoea (OSA) occurs because of recurrent narrowing and occlusion of the velopharynx (VP) during sleep. The speci®c cause of OSA is unknown. Cephalometric radiography, ®breoptic nasopharyngoscopy, acoustic re¯ec-tion techniques, and computerized tomography have limitations (dynamic and tridimensional evaluation) in the mechanism of occlusion investigation. Static and dynamic examination of the soft tissue structures surrounding the upper airway during the respiratory cycle in wakefulness and sleep, can lead to a better understanding of the process.Ultrafast magnetic resonance imaging (one image per 0.8 s) was used to study the upper airway and surrounding soft tissue in 17 patients with OSA during wakefulness and sleep, and in eight healthy subjects whilst awake.The major ®ndings of this investigation in the 25 subjects were as follows: 1) the VP was smaller in apnoeic patients, only during part of the respiratory cycle; 2) the variation in VP area during the respiratory cycle was greater in apnoeic patients than in controls, particularly during sleep, suggesting an increased compliance of the VP in these patients; 3) VP narrowing was similar in the lateral and anterior-posterior dimensions, both in controls and apnoeic patients while awake; apnoeic patients during sleep have a more circular VP upon reaching the minimum area; 4) there was an inverse relationship between dimensions of the lateral pharyngeal walls and airway area, probably indicating that lateral walls are passively compressed or stretched as a result of changes in the airway calibre; and 5) soft palate and parapharyngeal fatpads were larger in apnoeic patients, although their role in the genesis of OSA is uncertain.It was concluded that changes in the velopharynx area and diameter during the respiratory cycle are greater in apnoeic patients than in normal subjects, particularly during sleep. This suggests that apnoeic patients have a more collapsible velopharynx, this being the main mechanism of obstruction. Eur Respir J 2001; 17: 79±86. Obstructive sleep apnoea (OSA) occurs because of recurrent narrowing and occlusion of the upper airway during sleep [1], and the site of obstruction is most commonly at the level of the velopharynx (VP). Unfortunately, the speci®c cause of this obstruction is unknown [2±4]. Cephalometric analysis [5,6], which provides information on the morphology of the upper airway, does not allow dynamic evaluation. Fibreoptic nasopharyngoscopy with the Mu È ller manoeuvre [4,7,8] allows a dynamic evaluation of the pharyngeal airway, but is usually performed with the patient awake, and the changes in pressure and shape during the manoeuvre are not necessarily representative of the physiological changes during quiet breathing. Acoustic re¯ection has been used to demonstrate increased effective compliance of the pharynx during wakefulness in OSA patients in response to changes in pharyngeal intraluminal pressure and lung volume [9,10]. A major limitation of the acoustic re¯ection technique is its inabi...

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins.

Primary ciliary dyskinesia (PCD), or immotile cilia syndrome (ICS), 3p, 4q, 5p, 7p, 8q, 10p, 11q, 13q, 15q, 16p, 17q and 19q. Linkage analysis using PCD families with a dynein arm deficiency provided 'suggestive' evidence for linkage to chromosomal regions 8q, 16pter, while analyses using only PCD families with situs inversus resulted in 'suggestive' scores for chromosomes 8q, and 19q.