Mini-Symposium: Primary Ciliary DyskinesiaCiliary defects and genetics of primary ciliary dyskinesia
Introduction
The history of primary ciliary dyskinesia (PCD) began in the 20th century when A. Siewert noticed the surprising association of bronchiectasis and situs inversus1. In 1933, this association was formalised by M. Kartagener who described the triad of sinusitis, bronchiectasis, and situs inversus. Some forty years later, B. Afzelius identified in the axoneme of respiratory cilia and sperm flagella of patients with Kartagener syndrome the underlying ultrastructural defect corresponding to an absence of dynein arms2. By the end of the 20th century, DNAI1, the human ortholog of the Chlamydomonas reinhardtii gene IC78, was identified as the first gene involved in PCD3, thereby opening up a new field of research to decipher the pathophysiology of this complex disorder.
Section snippets
Ciliary structure
Cilia are evolutionarily conserved complex structures that protrude from the apical surface of most eukaryotic cells4. These organelles, which are structurally related to the flagella of spermatozoa, can be classified according to the arrangement of their microtubule cytoskeleton core, called axoneme. The axoneme consists either of nine doublets only («9+0» pattern) or of nine outer-doublet microtubules surrounding a central pair of single microtubules («9+2» pattern). The «9+0» primary cilia
Ciliary defects
Cilia play key physiological roles in diverse cell types and organisms. In mammals, defects in primary cilia cause a wide range of developmental disorders such as cystic diseases of liver, kidney and pancreas, and/or sensorial disorders, while motile cilia are involved in the most prominent ciliopathy called primary ciliary dyskinesia (PCD). PCD (MIM 242650) is a rare respiratory disease due to impaired mucociliary clearance resulting from functional and ultrastructural abnormalities of
PCD inheritance
In most instance, the transmission pattern of PCD is as an autosomal recessive inheritance of the disease11, although rare families showing autosomal dominant or X-linked modes of inheritance have also been reported27, 28, 29. The incidence of PCD ranges from 1/15,000 to 1/60,000 alive births11, while that of Kartagener syndrome is estimated to range between 1/20,000 and 1/30,000 alive births. However, the frequency of the disease is markedly underestimated, especially when situs inversus is
PCD genes (Table 1)
DNAI1, which is located in the p21-p23 region of chromosome 9, comprises 20 exons spanning about 62 kb of genomic DNA. It encodes a 699-amino-acid protein orthologous to the Chlamydomonas ODA protein IC78. Mutations in DNAI1 have been found in several PCD patients including patients with Kartagener syndrome3, 30, 31, 32. Although allelic heterogeneity was noted in the very first studies, it was secondarily shown that the IVS1+2_3insT mutation, which accounts for about half the mutated alleles,
Conclusion
The molecular basis of PCD is just beginning to be elucidated. To date, despite substantial efforts made for many years by several groups and the recent availability of huge sequence information, only six genes (DNAI1, DNAH5, DNAH11, RPGR, TXNDC3 and DNAI2) have been clearly implicated in PCD. Two of them, DNAI1 and DNAH5, which underlie the disease in about 25% of the patients with PCD, represent major genes, while three others (RPGR, DNAH11, TXNDC3), are “minor” genes, implicated in only few
Note added in proof
Just recently, 3 additional genes have been implicated in PCD: KTU in 2 families in which the patients display an absence of both dynein arms (Omran et al., Nature 2008; 456: 611–17); RSPH9 and RSPH4A in a few patients without situs inversus and in whom the main defect concern the central microtubular pair (Castleman et al., Am J Hum Genet 2009; 84: 197–209)
Acknowledgments
This work was supported by grants from the Legs Poix from the Chancellerie des Universités, the Assistance Publique-Hôpitaux de Paris (PHRC AOM06053, P060245) and the Agence Nationale pour la Recherche (ANR-05-MRAR-022-01).
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2017, Seminars in Radiation OncologyCitation Excerpt :This gene encodes the dynein, axonemal, and heavy chain 5 protein that is part of a protein complex that is associated with microtubule formation. Mutations in DNAH5 can result in primary ciliary dyskinesia resulting from abnormal cellular cilia and flagella.43 This gene is expressed in both the kidney and bladder, consistent with a possible role in the function of these organs.42