Ciliary defects and genetics of primary ciliary dyskinesia

doi:10.1016/j.prrv.2009.02.001

Paediatric Respiratory Reviews

Volume 10, Issue 2, June 2009, Pages 51-54

https://doi.org/10.1016/j.prrv.2009.02.001 Get rights and content

Abstract

Cilia are evolutionarily conserved structures that play key roles in diverse cell types. Motile cilia are involved in the most prominent ciliopathy called primary ciliary dyskinesia (PCD) that combines respiratory symptoms, male infertility, and, in nearly 50% cases, situs inversus. The diagnosis of PCD relies on the identification of ciliary abnormalities that mainly concern outer and/or inner dynein arms (ODA, IDA). PCD is a genetic condition, usually inherited as an autosomal recessive trait. To date, six genes have been clearly implicated in PCD. Two “major” genes, DNAI1 and DNAH5, underlie PCD in nearly half of the patients with ODA defects, whereas RPGR, DNAH11 and TXNDC3 are implicated in rare families with specific phenotypes (retinitis pigmentosa, abnormal beating of structurally normal cilia, and situs ambiguous, respectively). The relative contribution of DNAI2 is currently being assessed. In all the other patients with ODA or other ultrastructural defects, the causative genes remain to be identified.

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).

References (51)

G. Pennarun 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)
M.E. Porter
Axonemal dyneins: assembly, organization, and regulation
Curr Opin Cell Biol
(1996)
M.A. Chilvers et al.
Ciliary beat pattern is associated with specific ultrastructural defects in primary ciliary dyskinesia
J Allergy Clin Immunol
(2003)
C. Guichard et al.
Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome)
Am J Hum Genet
(2001)
N.T. Loges et al.
DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm
Am J Hum Genet
(2008)
Siewert
Ueber einen Fall von Bronchiectasie bei einem Patienten mit situs inversus viscerum
Berliner Klinische Wochenschrift
(1904)
M. Kartagener
Zur Pathogenese der Bronchiektasien. Bronchiektasien bei situs inversus viscerum
Beitr Klin Tuberk
(1933)
L.T. Haimo et al.
Cilia, flagella, and microtubules
J Cell Biol
(1981)
P. Satir et al.
Overview of structure and function of mammalian cilia
Annu Rev Physiol
(2007)
P. Hook et al.
The dynein family at a glance
J Cell Sci
(2006)

J.L. Rosenbaum et al.

Intraflagellar transport

Nat Rev Mol Cell Biol

(2002)

B.A. Afzelius

A human syndrome caused by immotile cilia

Science

(1976)

C.M. Rossman et al.

Immotile cilia syndrome in persons with and without Kartagener's syndrome

Am Rev Respir Dis

(1980)

B.A. Afzelius

The immotile-cilia syndrome: a microtubule-associated defect

CRC Crit Rev Biochem

(1985)

P.G. Noone et al.

Primary ciliary dyskinesia: diagnostic and phenotypic features

Am J Respir Crit Care Med

(2004)

R.U. De Iongh et al.

Ciliary defects in healthy subjects, bronchiectasis, and primary ciliary dyskinesia

Am J Respir Crit Care Med

(1995)

M. Jorissen et al.

Ultrastructural expression of primary ciliary dyskinesia after ciliogenesis in culture

Acta Otorhinolaryngol Belg

(2000)

A. Tamalet et al.

Abnormal central complex is a marker of severity in the presence of partial ciliary defect

Pediatrics

(2001)

C.M. Rossman et al.

The dyskinetic cilia syndrome; abnormal ciliary motility in association with abnormal ciliary ultrastructure

Chest

(1981)

M. Pedersen et al.

Rhinitis, sinusitis and otitis media in Kartagener's syndrome (primary ciliary dyskinesia)

Clin Otolaryngol

(1982)

M.A. Chilvers et al.

Functional analysis of cilia and ciliated epithelial ultrastructure in healthy children and young adults

Thorax

(2003)

D. Escalier et al.

Abnormalities of the ciliary axonemal complex in children: an ultrastructural cinetic study in a series of 34 cases

Biol Cell

(1982)

J. Chao et al.

Genetic heterogeneity of dynein-deficiency in cilia from patients with respiratory disease

Am Rev Respir Dis

(1982)

M. Fliegauf et al.

Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia

Am J Respir Crit Care Med

(2005)

M.E. Porter et al.

The 9 + 2 axoneme anchors multiple inner arm dyneins and a network of kinases and phosphatases that control motility

J Cell Biol

(2000)

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Mini-Symposium: Primary Ciliary DyskinesiaCiliary defects and genetics of primary ciliary dyskinesia

Abstract

Introduction

Section snippets

Ciliary structure

Ciliary defects

PCD inheritance

PCD genes (Table 1)

Conclusion

Note added in proof

Acknowledgments

Am J Hum Genet

Curr Opin Cell Biol

J Allergy Clin Immunol

Am J Hum Genet

Am J Hum Genet

Ueber einen Fall von Bronchiectasie bei einem Patienten mit situs inversus viscerum

Berliner Klinische Wochenschrift

Zur Pathogenese der Bronchiektasien. Bronchiektasien bei situs inversus viscerum

Beitr Klin Tuberk

Cilia, flagella, and microtubules

J Cell Biol

Overview of structure and function of mammalian cilia

Annu Rev Physiol

The dynein family at a glance

J Cell Sci

Intraflagellar transport

Nat Rev Mol Cell Biol

A human syndrome caused by immotile cilia

Science

Immotile cilia syndrome in persons with and without Kartagener's syndrome

Am Rev Respir Dis

The immotile-cilia syndrome: a microtubule-associated defect

CRC Crit Rev Biochem

Primary ciliary dyskinesia: diagnostic and phenotypic features

Am J Respir Crit Care Med

Ciliary defects in healthy subjects, bronchiectasis, and primary ciliary dyskinesia

Am J Respir Crit Care Med

Ultrastructural expression of primary ciliary dyskinesia after ciliogenesis in culture

Acta Otorhinolaryngol Belg

Abnormal central complex is a marker of severity in the presence of partial ciliary defect

Pediatrics

The dyskinetic cilia syndrome; abnormal ciliary motility in association with abnormal ciliary ultrastructure

Chest

Rhinitis, sinusitis and otitis media in Kartagener's syndrome (primary ciliary dyskinesia)

Clin Otolaryngol

Functional analysis of cilia and ciliated epithelial ultrastructure in healthy children and young adults

Thorax

Abnormalities of the ciliary axonemal complex in children: an ultrastructural cinetic study in a series of 34 cases

Biol Cell

Genetic heterogeneity of dynein-deficiency in cilia from patients with respiratory disease

Am Rev Respir Dis

Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia

Am J Respir Crit Care Med

The 9 + 2 axoneme anchors multiple inner arm dyneins and a network of kinases and phosphatases that control motility

J Cell Biol

Mini-Symposium: Primary Ciliary Dyskinesia
Ciliary defects and genetics of primary ciliary dyskinesia