RECENT ADVANCESCilia, primary ciliary dyskinesia and molecular genetics
Section snippets
INTRODUCTION
Primary ciliary dyskinesia (PCD) is a term used to describe the conditions that result from a primary defect in the structure or function of cilia. Apart from a few exceptional cases, PCD is predominantly inherited as an autosomal recessive condition.1., 2. It includes Kartagener syndrome, immotile cilia syndrome and ciliary orientation defects.3 PCD is a phenotypically and genetically heterogeneous condition, and several genetic mutations have already been described.4 Molecular genetic
CILIA
Cilia are highly complex organelles that are structurally related to the flagella of sperm and protozoa (e.g., C. reinharditi).5 They are composed of over 200 different polypeptides and can be subdivided into two main types: epithelial cilia; and primary cilia.
Epithelial cilia are hair-like appendages that line the human respiratory tract, female oviduct, male ductuli efferentes and ependyma of the brain. These cilia are motile and possess an intrinsic ciliary beat pattern and variable
Ciliary beat
The relative sliding of microtubule doublets generates the ciliary beat, with the outer dynein arm controlling beat frequency and the inner dynein arm the waveform. The central pair (CP) microtubules interact with the radial spokes (RS) to selectively activate subsets of dynein arms.12., 28. The CP/RS complex is the key regulator of dynein activity, and Chlamydomonas mutants lacking these structures are completely paralysed.29 The CP/RS complex can be demonstrated to respond to changes in ATP
Clinical features
PCD patients have recurrent sinopulmonary infections secondary to a failure in mucociliary defence mechanisms. Men may have reduced fertility due to sperm immotility or abnormalities of the vas deferens, and about 50% of all affected patients have laterality defects such as situs inversus. The symptoms of PCD are present from birth, but there is a significant variation in both the severity of symptoms and the age at which the condition is diagnosed.36 There is a recognised association with
Identified loci and genetic mutations
Genetic linkage analysis and mutational studies in PCD patients have shown that this disease is genetically heterogeneous even within specific ultrastructural phenotypes.4., 41. The only ultrastructural phenotype for which genetic mutations have been identified is that of an outer dynein arm (ODA) defect. The three genes in which mutations have been characterised are DNAI1, DNAH5 and DNAH11 located on human chromosomes 9p, 5p and 7p, respectively.42., 43., 44., 45., 46. These genes encode a
IMPLICATIONS OF CLONING PCD GENE(S)
The identification of PCD genes will provide new insights into the molecular mechanisms involved in the assembly and function of cilia, the determination of laterality and the development of new methods for diagnosis and treatment of PCD. The association of PCD with laterality defects has been partially explained by the identification of nodal cilia, but the exact way in which cilia function and left-right axis determination are related remains a critical question in developmental biology.
There
THE IMPACT OF THE HUMAN GENOME PROJECT
The human genome encodes an estimated 35 000 genes60., 61. and, as a result of the HGP, sequencing is now 99% complete. The HGP also facilitated the development of unique bioinformatics tools that can be defined as a collection of statistical methods for dealing with large biological data sets. This has accelerated the identification and characterisation of new and known disease genes, and has provided essential resources for the approaches used to identify PCD genes.
The Basic Local Alignment
PRACTICE POINTS
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PCD is a genetically and ultrastructurally heterogeneous condition, which is usually recessively inherited.
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PCD should be considered as a diagnosis in patients with sinopulmonary infections in association with neonatal symptoms and persistent rhinitis.
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Cilia have a role in left-right axis patterning, and this is due to the embryonic role of nodal cilia.
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Genetic mutations have been identified in PCD patients with outer dynein arm defects: DNAH5 on chromosome 5p and DNAI1 on chromosome 9p. Mutations
RESEARCH DIRECTIONS
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Increased use of bioinformatics tools such as The Basic Local Alignment Search Tool to identify candidate genes in PCD.
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Cilia proteomics and the mapping of ciliary genes within the human genome.
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Identification, characterisation and mapping of the enzymes and proteins involved in ciliary construction and regulation.
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Detailed studies of the association between nodal cilia function and body axis determination.
References (66)
Flagellar assembly in two hundred and fifty easy to follow steps
Trend. Genet.
(1995)- et al.
Local mucociliary defence mechanisms
Paediat. Respir. Rev.
(2000) - et al.
The vertebrate primary cilium is a sensory organelle
Curr. Opin. Cell Biol.
(2003) - et al.
Randomisation of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein
Cell
(1998) - et al.
Intraflagellar transport and cilia-dependent diseases
Trends Cell Biol.
(2002) - et al.
An autosomal recessive polycystic kidney disease gene homolog is involved in intraflagellar transport in C. elegans ciliated sensory neurons
Curr. Biol.
(2001) Mechanisms of left-right asymmetry: what’s right and what’s left?
Dev. Cell
(2001)- et al.
Lateralization defects and ciliary dyskinesia: lessons from algae
Trends Genet
(2003) - et al.
Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia
Am. J. Hum. Genet.
(1999) - et al.
Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome)
Am. J. Hum. Genet.
(2001)