Ciliary Dyskinesia, Primary, 1

A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-1 (CILD1) is caused by compound heterozygous mutation in the DNAI1 gene (604366) on chromosome 9p13.

Description

Primary ciliary dyskinesia is a genetically heterogeneous autosomal recessive disorder resulting from loss of function of different parts of the primary ciliary apparatus, most often dynein arms. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus (270100), and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003).

Genetic Heterogeneity of Primary Ciliary Dyskinesia

Other forms of primary ciliary dyskinesia include CILD2 (606763), caused by mutation in the DNAAF3 gene (614566) on 19q13; CILD3 (608644), caused by mutation in the DNAH5 gene (603335) on 5p15; CILD4 (608646), mapped to 15q13; CILD5 (608647), caused by mutation in the HYDIN gene (610812) on 16q22; CILD6 (610852), caused by mutation in the TXNDC3 gene (607421) on 7p14; CILD7 (611884), caused by mutation in the DNAH11 gene (603339) on 7p15; CILD8 (612274), mapped to 15q24-q25; CILD9 (612444), caused by mutation in the DNAI2 gene (605483) on 17q25; CILD10 (612518), caused by mutation in the DNAAF2 gene (612517) on 14q21; CILD11 (612649), caused by mutation in the RSPH4A gene (612647) on 6q22; CILD12 (612650), caused by mutation in the RSPH9 gene (612648) on 6p21; CILD13 (613193), caused by mutation in the DNAAF1 gene (613190) on 16q24; CILD14 (613807), caused by mutation in the CCDC39 gene (613798) gene on 3q26; CILD15 (613808), caused by mutation in the CCDC40 gene (613799) on 17q25; CILD16 (614017), caused by mutation in the DNAL1 gene (610062) on 14q24; CILD17 (614679), caused by mutation in the CCDC103 gene (614677) on 17q21; CILD18 (614874), caused by mutation in the DNAAF5 gene (614864) on 7p22; CILD19 (614935), caused by mutation in the LRRC6 gene (614930) on 8q24; CILD20 (615067), caused by mutation in the CCDC114 gene (615038) on 19q13; CILD21 (615294), caused by mutation in the DRC1 gene (615288) on 2p23; CILD22 (615444), caused by mutation in the ZMYND10 gene (607070) on 3p21; CILD23 (615451), caused by mutation in the ARMC4 gene (615408) on 10p; CILD24 (615481), caused by mutation in the RSPH1 gene (609314) on 21q22; CILD25 (615482), caused by mutation in the DYX1C1 gene (608706) on 15q21; CILD26 (615500), caused by mutation in the C21ORF59 gene (615494) on 21q22; CILD27 (615504), caused by mutation in the CCDC65 gene (611088) on 12q13; CILD28 (615505), caused by mutation in the SPAG1 gene (603395) on 8q22; CILD29 (615872), caused by mutation in the CCNO gene (607752) on 5q11; CILD30 (616037), caused by mutation in the CCDC151 gene (615956) on 19p13; CILD32 (616481), caused by mutation in the RSPH3 gene (615876) on 6q25; CILD33 (616726), caused by mutation in the GAS8 gene (605178) on 16q24; CILD34 (617091), caused by mutation in the DNAJB13 gene (610263) on 11q13; CILD35 (617092), caused by mutation in the TTC25 gene (617095) on 17q21; CILD36 (300991), caused by mutation in the PIH1D3 gene (300933) on Xq22; CILD37 (617577), caused by mutation in the DNAH1 gene (603332) on 3p21; CILD38 (618063), caused by mutation in the CFAP300 gene (618058) on 11q22; CILD39 (618254), caused by mutation in the LRRC56 gene (618227) on 11p15; CILD40 (618300), caused by mutation in the DNAH9 gene (603330) on 17p12; and CILD41 (618449), caused by mutation in the GAS2L2 gene (611398) on 17q12.

Ciliary abnormalities have also been reported in association with both X-linked and autosomal forms of retinitis pigmentosa. Mutations in the RPGR gene (312610), which underlie X-linked retinitis pigmentosa (RP3; 300029), are in some instances (e.g., 312610.0016) associated with recurrent respiratory infections indistinguishable from immotile cilia syndrome; see 300455.

Afzelius (1979) gave an extensive review of cilia and their disorders. There are also several possibly distinct CILDs described based on the electron microscopic appearance of abnormal cilia, including CILD with transposition of the microtubules (215520), CILD with excessively long cilia (242680), and CILD with defective radial spokes (242670).

Clinical Features

Kartagener, an internist in Zurich, and Horlacher described a familial form of bronchiectasis with dextrocardia and nasal polyps (Kartagener and Horlacher, 1936). Kartagener and Stucki (1962) found 334 cases in the literature and added 2 more cases of bronchiectasis with situs inversus.

Arge (1960) described transposition of the viscera and sterility in men.

Afzelius et al. (1975) and Afzelius (1976) reported a total of 3 patients with chronic sinusitis, bronchitis, and frequent pneumonias, colds, and ear infections since childhood. Two patients had bronchiectasis. All 3 patients also had situs inversus totalis. The 3 patients, and a brother of 1 of them, also had immotile spermatozoa, with the sperm tail appearing straight and stiff. Studies of tracheobronchial clearance showed no mucociliary transport, and studies of a bronchial mucosal biopsy of 1 patient showed no ciliary motion. Electron microscopy of the respiratory cilia and sperm showed scarce or absent dynein arms. Dynein arms normally form temporary cross bridges between ciliary filaments, and likely aid in generating movement in cilia and sperm tails. Afzelius (1976) concluded that the primary defect was in the production or function of dynein arms, which resulted in immotility with secondary recurrent infections. He further postulated that normal visceral symmetry is determined by movement of cilia in certain embryonic epithelial tissues. Absence of normal ciliary movement from lack of dynein arms results in lack of definitive patterning; thus, chance alone would determine whether the viscera take up the normal or reversed position during embryogenesis. This hypothesis can explain why approximately half of familial cases of immotile cilia syndrome have situs inversus.

Afzelius (1976) noted that semi-sterility of affected females had been observed.

Eliasson et al. (1977) investigated 6 men and a woman with congenital immotility of cilia. All had chronic airway infections and the men had immotile spermatozoa. The woman and 3 men had situs inversus, consistent with a diagnosis of Kartagener syndrome. Mucociliary transport was significantly delayed in all patients, and the sperm tails lacked dynein arms in 5 men. Respiratory cilia from the women and 2 men lacked dynein arms and were irregularly oriented. The results supported the hypothesis that a congenital defect in the cilia and sperm tails resulted in chronic respiratory tract infections and male sterility. Approximately half of these patients have Kartagener syndrome. Eliasson et al. (1977) concluded that the gene involved may control normal situs. This control may be lacking in homozygotes such that situs is random.

Waite et al. (1978) reported that Polynesian New Zealand Maori and Samoan Islanders with bronchiectasis had decreased or absent pulmonary mucociliary clearance and immotile sperm. Electron microscopy showed a defect in dynein arms in both sperm tails and pulmonary cilia. None had dextrocardia. Waite et al. (1981) found that ciliated bronchial or nasal epithelium from 20 Polynesian bronchiectatic patients showed partial or complete loss of dynein arms when examined by electron microscopy. Many patients had other ciliary abnormalities, with over 25% of cilia affected. Bronchiectasis tended to progress even after segmental resection. A population-based survey indicated a rate of bronchiectasis of 600 per 100,000. This same survey showed dextrocardia in 9 of 56,000 persons, none of whom showed radiologic evidence of bronchiectasis.

Guerrant et al. (1978) noted that patients with the immotile cilia syndrome may present with bronchiectasis, sinusitis, and infertility; dextrocardia may not be present.

Neustein et al. (1980) reported a patient with absence of only the inner dynein arm in respiratory cilia, rather than total absence of the dynein arms. The patient had repair of duodenal atresia at birth.

Jonsson et al. (1982) described a 21-year-old man with recurrent sinusitis, bronchitis, and otitis media, and situs inversus viscerum including left-sided appendix with appendicitis at age 12. He had a normal 4-year-old son. Electron microscopy of nasal and bronchial mucosa in the proband showed abnormal orientation of the basal processes of the cilia and absent dynein arms, but completely normal sperm.

Schidlow et al. (1982) reported a family in which 1 sib had Kartagener syndrome and another had the polysplenia syndrome (208530). Only a small percentage (less than 20%) of the respiratory cilia of these 2 children were abnormal. Two female third cousins had Kartagener syndrome. Schidlow and Katz (1983) noted that structurally normal respiratory cilia may be found in otherwise typical Kartagener syndrome.

Eavey et al. (1986) found significantly fewer ciliary outer dynein arms in all 4 patients with full-blown Kartagener syndrome and in 2 of 5 patients with sinusitis and bronchiectasis but no dextrocardia. No changes were found in carriers or in any other persons studied. The count of outer dynein arms was consistent in a given individual.

Samuel (1987) reported a 26-year-old man with typical Kartagener syndrome except for the presence of normal spermatozoa. He had chronic sinopulmonary symptoms, situs inversus, and absent frontal sinuses, while his spermatozoa had normal motility, ultrastructure, and fertilizing capacity. Repeated brush biopsies of the bronchial epithelium showed only keratinized squamous epithelium and no ciliated cells. The patient had a twin brother, probably monozygotic, who died in early infancy following a respiratory infection.

Noone et al. (1999) reported monozygotic twin women with primary ciliary dyskinesia associated with bronchiectasis, chronic sinusitis, and middle ear disease. Ciliary ultrastructural analysis showed deficiency of the inner dynein arms. One of the twins had situs solitus, and the other had situs inversus totalis. The findings were considered consistent with the hypothesis that situs inversus occurring in patients with primary ciliary dyskinesia is a random but 'complete' event in the fetal development of patients with this disorder.

Other Features

Holmes et al. (1968) found low serum levels of gamma A globulin in some patients with Kartagener syndrome.

Patients with the Kartagener syndrome may have anosmia (Goldstein, 1979).

Afzelius (1979) pointed out that the ependyma of the brain is ciliated epithelium: '....two-thirds of the investigated persons complained about rather severe, chronic headaches, and...many had sought medical advice for this complaint. Some regarded the headaches as the symptom that caused the greatest suffering.'

Gagnon et al. (1980, 1982) found reduced protein-carboxyl methylation in infertile males with immotile sperm. They studied protein-carboxyl methylase (EC 2.1.1.24) because it is an enzyme involved in the regulation of cellular locomotion in both bacteria and leukocytes. Low enzyme activity in 9 infertile patients with nonmotile spermatozoa was, they thought, not due to a primary genetic defect, since the enzyme activity was normal in red cells of these patients and spontaneous recovery of motility was associated with return of enzyme activity. Of the 9 patients, 2 had bronchiectasis, 1 with sinusitis and dextrocardia and the electron microscopic changes of the Kartagener syndrome in sperm tails.

Knudsen et al. (1983) and Valerius et al. (1983) found depressed motility of neutrophils in 10 patients with primary ciliary dyskinesia, 6 of whom had Kartagener syndrome. They suggested that impaired leukocyte function, like ciliary dysfunction, may be due to abnormality of microtubules and may contribute to increased susceptibility to respiratory infections in these patients.

Kosaki et al. (2004) reported a family in which 3 fetuses, born to healthy, nonconsanguineous parents, had ventriculomegaly, situs abnormality, or both. The male proband fetus had hydrocephalus, a 3-lobed left lung, and defective tracheal cilia with absent inner dynein arms and a single centriole. The other 2 fetuses were a male with ventriculomegaly and a female with situs abnormality and likely hydrocephalus, both of whom had the same ciliary defect as the proband. The presence of 3 affected fetuses of both sexes in a family with phenotypically normal parents suggested autosomal recessive inheritance. Kosaki et al. (2004) noted that primary ciliary dyskinesia with hydrocephalus with or without situs abnormalities had been described in 3 sporadic cases (Greenstone et al., 1984; De Santi et al. (1990); Picco et al., 1993) and in 3 families (al-Shroof et al., 2001; Wessels et al., 2003).

Inheritance

Gorham and Merselis (1959) concluded that Kartagener syndrome is inherited as a recessive with incomplete penetrance.

Moreno et al. (1965) identified Kartagener syndrome in 2 of 5 offspring of first-cousin parents. Another sib had bronchiectasis, as did the father, and the other 2 children were 'chronic coughers.' The findings suggested autosomal recessive inheritance of the full disorder.

Moreno and Murphy (1981) stated that there is a striking discrepancy between predictions for autosomal recessive inheritance and actual segregation ratio of cases of Kartagener syndrome in the families of affected individuals. Studies in mice have suggested that situs inversus is inherited as an autosomal recessive trait with reduced penetrance. Moreno and Murphy (1981) reexamined the surmised autosomal recessive inheritance of situs inversus, and suggested that given the homozygous genotype, the phenotypic lateralization is as likely to be left as to be right. The segregation ratio in the progeny of 2 carriers would then be not one-fourth but one-eighth. This concept supposed that there is a component in normal human lateralization that is under the control of a single genetic locus. When this is disturbed, the direction of rotation becomes random. Moreno and Murphy (1981) concluded that Kartagener syndrome, or situs inversus, is an autosomal recessive condition with 50% random probability of clinical manifestation.

Diagnosis

Prenatal Diagnosis

Wessels et al. (2003) reported that mild fetal cerebral ventriculomegaly can be a prenatal sonographic marker for primary ciliary dyskinesia or Kartagener syndrome.

Clinical Management

Women with Kartagener syndrome are fertile, which speaks against the notion that ciliary currents waft eggs down the fallopian tube. The spermatozoa from Kartagener patients are normal; if micromanipulated so that they come to lie adjacent to the plasma membrane of the oocyte, they will fuse with the membrane and fertilize the egg (Aitken et al., 1983). Thus, in vitro fertilization may be a possibility in such patients.

In 2 men with Kartagener syndrome and immotile sperm, von Zumbusch et al. (1998) achieved the birth of healthy children after intracytoplasmic sperm injection into the ova of their wives.

Miralles et al. (1992) presented a method of overcoming some of the technical difficulties of heart-lung transplantation in situs inversus. Macchiarini et al. (1994) reported en bloc double lung transplantation with bilateral bronchial anastomoses in 3 patients with complete situs inversus and end-stage lung disease. One patient died of obliterative bronchiolitis 36 months after the operation. The remaining 2 were alive and doing well after 48 months. The patients were a 41-year-old woman, a 38-year-old man, and a 49-year-old man.

Pathogenesis

Among 38 patients with immotile cilia syndrome, including 20 with situs inversus, Afzelius (1981) identified 5 types of deficits on the basis of specific electron microscopic changes. A reduction in the number of dynein arms was the most frequently encountered abnormality (14 cases). In 2 cases, dynein arms were completely absent. In 1 case, the spokes were defective and, as a consequence, the 2 microtubular singlets took an eccentric rather than central position in the cilia. In 2 cases, no ultrastructural defects of the cilia were detected, but the cilia lacked a fixed orientation. In 9 cases, cilia showed a normal ultrastructure, but many cases showed compound cilia, which was considered a nonspecific finding. Afzelius (1981) noted that corneal abnormalities, headaches, and a poor sense of smell in the immotile cilia syndrome could be attributed to the primary defect. The inside of the cornea is monociliated; each cell carries a single cilium. Studies in Sweden, France, and Canada indicate that lack of dynein arms is the most common cause of the immotile cilia syndrome.

Rott (1983) listed 7 types of primary ciliary dyskinesia based on different axonemal defects found in 6 of them and 'no visible change' in a seventh. The most frequent form (type I), accounting for 74% of cases, was characterized by lack of both dynein arms. Affected sibs, supporting recessive inheritance, had been observed in types I, IV (lack of spoke structures), and V (lack of central structures). Rott (1983) suggested that there may be instances of new dominant mutations.

In a review, Palmblad et al. (1984) listed 10 different ultrastructural abnormalities in the axonemal microtubular apparatus that have been observed as underlying the immotile cilia syndrome.

Molecular Genetics

In a patient with primary ciliary dyskinesia, Pennarun et al. (1999) identified 2 loss-of-function mutations in the DNAI1 gene (604366.0001-604366.0002). The patient was a 9-year-old boy, born to unrelated parents, who presented in early childhood with chronic respiratory symptoms characterized by chronic sinusitis, serous otitis, and recurrent episodes of bronchitis associated with severe segmental atelectasis that necessitated partial lobectomy. There was no family history of a similar disorder and no evidence of situs inversus. No ciliary beating was observed in samples of trachea mucosa, and transmission electron microscopy showed the absence of outer dynein arms in all cilia. Pennarun et al. (1999) excluded linkage between the DNAI1 gene and similar phenotypes in 5 other unrelated, consanguineous families, providing a clear demonstration of locus heterogeneity.

Guichard et al. (2001) described a patient with Kartagener syndrome who was compound heterozygous for mutations in the DNAI1 gene (604366.0001; 604366.0003). The proband's brother had recurrent upper and lower respiratory tract infections and sterility without situs inversus. Repeated spermograms demonstrated immotile spermatozoa flagella. Both brothers also had ureteral lithiasis. The cilia of the brother showed absent or truncated outer dynein arms. A second patient with Kartagener syndrome had situs inversus totalis, chronic sinusitis, bronchitis, recurrent otitis, and aplasia of the frontal sinus. She was found to be compound heterozygous for 2 mutations in the DNAI1 gene (604366.0001; 604366.0004).

Associations Pending Confirmation

For discussion of a possible association between primary ciliary dyskinesia and variation in the DNAH8 gene, see 603337.0001.

Heterogeneity

Afzelius (1980, 1987) suggested that the immotile cilia syndrome is a cluster of disorders analogous to lysosomal, mitochondrial, or peroxisomal disorders and that there are only 2 phenotypes: cilia immobility with and without situs inversus. Those with situs inversus, known as Kartagener syndrome, represent about 50% of cases. All cases have absence of either dynein arms or the spokes of the axoneme of cilia and sperm tails; absent dynein arms presumably reflect abnormal dyneins or abnormal dynein-binding proteins, defect in any one of which could result in the same pathologic consequences. Since the cilium is constructed of some 100 different polypeptides, there is ample room for genetic heterogeneity.

In a patient with clinically typical immotile cilia syndrome, Jahrsdoerfer et al. (1979) found no cilia in biopsies taken from 3 areas that are normally ciliated. In contrast, Herzon and Murphy (1980) reported a patient with the typical clinical features of Kartagener syndrome in whom ultrastructure of cilia showed no abnormalities even though ciliary function was abnormal. These diverse findings suggested genetic heterogeneity of the disorder.

Sturgess et al. (1986) analyzed 46 patients, including 20 males and 26 females, with primary ciliary dyskinesia from 38 families. Situs inversus was present in 26. The ultrastructural change in respiratory tract cilia was deficiency in outer dynein arms (in 19), inner dynein arms (in 3), both inner and outer dynein arms (in 15), and radial spokes (in 5), and involved a microtubular transposition anomaly in 4. Segregation analysis was consistent with autosomal recessive inheritance. The finding of various structural defects suggested several genetic determinants. Examination of paternal age and birth order gave no evidence of new dominant mutation.

Because tubulin is the main protein component of microtubules, and because the tubulin beta gene (TUBB; 191130) had been assigned to chromosome 6p21, Bianchi et al. (1992) studied linkage with HLA on 6p21 in 2 Italian families, each with 2 affected sibs. All 4 affected sibs, a male and a female in one family and 2 females in the other, shared the HLA-DR7;DQw2 haplotype. Furthermore, linkage of an ICS susceptibility locus with HLA was suggested by the fact that the affected sibs were HLA-identical, whereas the healthy brother in the second family was HLA-different. (Note that CILD12 (612650) maps to 6p21). Volz et al. (1994) also suggested that the TUBB gene was a possible site of the mutation causing the HLA-linked form of immotile cilia syndrome. Gasparini et al. (1994) showed by segregation analysis that the motilin gene (MLN; 158270) on 6p21 was not the site of the mutation in HLA-associated ICS.

Narayan et al. (1994) described a family in which a mother and her 5 male children, the offspring of 3 different fathers, all had primary ciliary dyskinesia. None of the mother's marriages was consanguineous. The findings suggested either X-linked or autosomal dominant inheritance. Cytogenetic and fluorescence in situ hybridization analyses on the mother and 1 son showed no abnormality, specifically, on human chromosomes 12 and 14, which show syntenic homology with mouse chromosomes 6 and 12, carrying the hpy and iv mutations, respectively. One of the 6 affected individuals had dextrocardia; all had sinopulmonary symptoms with abnormalities of the cilia by electron microscopy. Narayan et al. (1994) reviewed reports of other families with inheritance patterns other than autosomal recessive.

Chapelin et al. (1997) noted that the genetic complexity of the ciliary apparatus may account for the failure to establish a reproducible linkage between this phenotype and a specific genetic region.

Blouin et al. (2000) performed a genomewide linkage search in 31 multiplex European and North American families with CILD including 70 affected individuals. No major locus for most of the families was identified, although the sample was powerful enough to detect linkage if 40% of the families were linked to one locus. These results strongly suggested extensive locus heterogeneity. The authors pointed to potential genomic regions on 12 chromosome arms harboring candidate loci.

Nomenclature

Kartagener syndrome is sometimes known as the Siewert syndrome (Siewert, 1904).

Eliasson et al. (1977) is credited with the term 'immotile cilia syndrome' (Afzelius, 2004).

In vitro studies have shown that various patterns of abnormal ciliary beating (Rossman et al., 1980; Rutland and Cole, 1980) are the most frequently observed abnormalities in the Kartagener syndrome and the immotile cilia syndrome. These authors concluded that the term 'dyskinetic cilia syndrome' may be a more appropriate term for this class of disorder.

History

Arvid Afzelius, the grandfather of B. Afzelius, who first observed the electron microscopic changes in Kartagener syndrome, probably was the first to report the disorder we now know as Lyme disease (Garfield, 1989; Afzelius, 1989). In the early 1900s, the grandfather reported a characteristic skin rash, which he termed erythema chronicum migrans, following bites of the tick Ixodes ricinus. Lyme disease in the United States and the less severe erythema migrans in Europe are caused by infection of related spirochetes injected by ticks. Berglund et al. (1995) reported that Lyme disease is very common in southern Sweden, with a relatively high frequency of neurologic complications and arthritis, but a lower incidence of carditis than is found in the United States.

Although most familial cases of Kartagener syndrome have been confined to sibs, Torgersen (1947) suggested dominant inheritance.

Mapping studies with blood groups were performed by Knox et al. (1960) and Cook et al. (1962) in families with Kartagener syndrome.

Liechti-Gallati and Kraemer (1995) excluded mutations in the CFTR gene (602421) in 5 patients with immotile cilia syndrome. Additional family studies of 1 patient found no linkage between the disorder and intragenic polymorphism or 4 flanking markers.

Kastury et al. (1997) hypothesized that the human homolog of the Chlamydomonas inner dynein arm gene, p28 (602135), could be a candidate gene for immotile cilia syndrome. Witt et al. (1999) excluded linkage to chromosome 7 in linkage studies of 23 families with Kartagener syndrome.

Animal Model

Stowater (1976) and Afzelius (1979) referred to Kartagener syndrome in the dog.

Bryan et al. (1977) found that mice homozygous for the hydrocephaly-polydactyly (hpy) mutation have a similar dynein defect in cilia and flagella. Bryan (1977) wrote that 'the A-tubules of the outer doublets appear to lack dynein arms.'

Fifty percent of mice homozygous for the iv mutation (see 603339) show situs inversus (Layton, 1976; Brueckner et al., 1989). Handel and Kennedy (1984) found no abnormality in the ultrastructure and motility of tracheal cilia or sperm tails in these mice. Layton (1986) speculated that the centriole may be the 'compass of the cell' and that the defect in these mice may be in the ability to read the compass.

Afzelius (1980) speculated that embryonic cilia bring the heart to the left side in the mid-fourth week in the mouse.

Merlino et al. (1991) created a transgenic mouse line exhibiting an immotile sperm syndrome that duplicated the features of Kartagener syndrome. The mice were generated by inserting the cDNA for a human epidermal growth factor receptor (EGFR; 131550) into the mouse genome, driven by the chicken beta-actin promoter. One of the resulting transgenic lines expressed extremely high levels of EGFR RNA in the testes but not in any other tissue examined. In situ hybridization studies indicated that the transgene was transcribed during meiosis, as early as the primary spermatocyte stage, whereas the appearance of human EGF receptors was delayed until the post-meiotic stages of sperm differentiation. About half the males homozygous for the transgene were infertile. Moreover, their infertility was associated with a lack of sperm motility due to disorganization of the axoneme.

Genetic heterogeneity has been well documented in Chlamydomonas, a unicellular green alga with 2 flagella that have the same axonemal structure as human bronchial cilia and sperm tails. Immotile strains of Chlamydomonas appear to have 'the same disease' as patients with primary ciliary dyskinesia. There are 3 immotile strains with different mutations as indicated by breeding experiments. All show identical defects by electron microscopy, namely defects in the central microtubular structures (Pennarun et al., 1999).