Genetics and Biology of Primary Ciliary Dyskinesia

Asthenozoospermia is a common cause of male infertility, but its etiology remains incompletely understood. We recruited three Pakistani infertile brothers, born to first-cousin parents, displaying idiopathic asthenozoospermia but no ciliary-related symptoms. Whole-exome sequencing identified a missense variant (c.G5408A, p.C1803Y) in DNAH17, a functionally uncharacterized gene, recessively cosegregating with asthenozoospermia in the family. DNAH17, specifically expressed in testes, was localized to sperm flagella, and the mutation did not alter its localization. However, spermatozoa of all three patients showed higher frequencies of microtubule doublet(s) 4-7 missing at principal piece and end piece than in controls. Mice carrying a homozygous mutation (Dnah17M/M) equivalent to that in patients recapitulated the defects in patients' sperm tails. Further examinations revealed that the doublets 4-7 were destabilized largely due to the storage of sperm in epididymis. Altogether, we first report that a homozygous DNAH17 missense variant specifically induces doublets 4-7 destabilization and consequently causes asthenozoospermia, providing a novel marker for genetic counseling and diagnosis of male infertility.

/pdf/a-dnah17-missense-variant-causes-flagella-destabilization-3p0kezt6hv.pdf

A DNAH17 missense variant causes flagella destabilization and asthenozoospermia.

Ciliopathies are a collection of disorders related to cilia dysfunction. Cilia are specialized organelles that project from the surface of most cells. Motile and primary (sensory) cilia are essential structures and have wide ranging functions. Our understanding of the genetics, pathophysiology, and clinical manifestations of motile ciliopathies, including primary ciliary dyskinesia (PCD), has rapidly advanced since the disease was linked to ciliary ultrastructural defects nearly five decades ago. We will provide an overview of different types of cilia, their role in child health and disease, focusing on motile ciliopathies, and describe recent advances that have led to improved diagnostics and may yield therapeutic targets to restore ciliary structure and function.

Understanding Primary Ciliary Dyskinesia and Other Ciliopathies.

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease, caused by specific primary structural and/or functional abnormalities of the motile cilia, in contrast with the transitory abnormalities seen in secondary ciliary dyskinesia. Disease-causing mutations in at least 16 genes have already been identified. The true incidence of PCD may be higher than currently reported, because the diagnosis is challenging and often missed. For the confirmation of PCD, both ciliary motility as well as ciliary ultrastructure must be evaluated. An early and adequate diagnosis and therapy can theoretically prevent bronchiectasis. Measurement of nasal nitric oxide has some value as a screening test but cannot be performed in young children. In the respiratory tract epithelium, impaired mucociliary clearance leads to chronic and/or recurrent upper and lower respiratory tract infections. In up to 75 % of the patients, respiratory manifestations start in the newborn period, although the diagnosis is often missed at that time. During embryogenesis, nodal cilia, which are motile cilia, determine the correct lateralization of the organs. Dysfunction of these cilia leads to random lateralization and thus situs inversus in approximately 50 % of the patients with PCD. The tail of a spermatozoon has a structure similar to that of a motile cilium. Consequently, male infertility due to immotile spermatozoa is often part of the characteristics of PCD. Given the heterogeneity and the rarity of the disorder, therapy is not evidence-based. Many treatment schedules are proposed in analogy with the treatment for cystic fibrosis. Respiratory infections, situs inversus and male infertility are typical manifestations of PCD, a rare autosomal recessive disorder.

Primary ciliary dyskinesia, an orphan disease

Primary ciliary dyskinesia (PCD) is a genetic disorder of motile cilia. Clinical features include chronic oto-sinopulmonary disease, laterality defects, and male fertility reflecting impaired function of respiratory cilia in the upper and lower respiratory tracts, nodal cilia in the embryonic node and sperm tails, respectively. Recent studies have identified over 40 PCD-associated genes that encode proteins involved in ciliary biogenesis, assembly, structure, or function. Mutations in these genes account for approximately 70% of PCD cases; therefore, further gene discovery is expected. The diagnosis of PCD is challenging because no single test has the required diagnostic accuracy. Recent efforts have focused on standardizing and validating a panel of tests (including assessment for key clinical features, nasal nitric oxide measurement, ciliary ultrastructure analysis, and PCD genetic testing) to be used at PCD Centers to accurately diagnose PCD. Multi-center research programs focused on PCD in North America and Europe have been crucial for PCD gene discovery, advancing our understanding of the natural history of PCD and launching multi-center clinical trials.

Primary Ciliary Dyskinesia (PCD): A genetic disorder of motile cilia.

To the Editors: 

In primary ciliary dyskinesia (PCD; Mendelian Inheritance in Man database #242650), a rare genetic disorder, the dysfunctional motility of cilia and impaired mucociliary clearance result in a myriad of clinical manifestations including recurrent infections of the respiratory tract, eventually causing lung damage, such as bronchiectasis, laterality defects and male infertility 1. The heterogeneous clinical presentation of PCD and the limitations of transmission electron microscopy (TEM) to assess ultrastructural defects within the cilium may delay the diagnosis 2. Ciliary beat frequency and pattern analyses and nasal nitric oxide (nNO) measurements are helpful 1, 3, 4, but only ciliogenesis in cultured cells has been reported as decisive for the diagnosis of the atypical PCD phenotype with normal axonemal ultrastructure 1, 5. Under these conditions, the identification of disease-causing mutations could overcome the current diagnostic limitations of TEM and improve our understanding of the biology and function of the cilium 2, 6, 7. For these reasons, we have assessed whether an analysis of the DNAH11 gene, in which some nonsense mutations have been reported to be associated with a normal axonemal ultrastructure but with an abnormal nonflexible beating pattern, reduced cilium bending capacity and a hyperkinetic beat 7, could be used to identify new mutations in three atypical PCD patients and thus be used in the diagnostic work-up of these most difficult cases.

We observed three patients (A and B, sister and brother; and C, male), at the ages of 15 yrs and 5 months, 9 yrs and 4 months, and 8 yrs, respectively. The two siblings presented situs inversus. Both patients had chronic respiratory symptoms which required repeated treatment with antibiotics. Patient A also had neonatal purulent rhinitis with frequent relapses, chronic rhinosinusitis and otitis …

https://erj.ersjournals.com/content/erj/35/6/1413.full.pdf

New DNAH11 mutations in primary ciliary dyskinesia with normal axonemal ultrastructure

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New DNAH11 mutations in primary ciliary dyskinesia with normal axonemal ultrastructure