Recessive HYDIN Mutations Cause Primary Ciliary Dyskinesia without Randomization of Left-Right Body Asymmetry

Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder characterized by defective cilia and flagella motility. Chronic destructive-airway disease is caused by abnormal respiratory-tract mucociliary clearance. Abnormal propulsion of sperm flagella contributes to male infertility. Genetic defects in most individuals affected by PCD cause randomization of left-right body asymmetry; approximately half show situs inversus or situs ambiguous. Almost 70 years after the hy3 mouse possessing Hydin mutations was described as a recessive hydrocephalus model, we report HYDIN mutations in PCD-affected persons without hydrocephalus. By homozygosity mapping, we identified a PCD-associated locus, chromosomal region 16q21-q23, which contains HYDIN. However, a nearly identical 360 kb paralogous segment (HYDIN2) in chromosomal region 1q21.1 complicated mutational analysis. In three affected German siblings linked to HYDIN, we identified homozygous c.3985G>T mutations that affect an evolutionary conserved splice acceptor site and that subsequently cause aberrantly spliced transcripts predicting premature protein termination in respiratory cells. Parallel whole-exome sequencing identified a homozygous nonsense HYDIN mutation, c.922A>T (p.Lys307(∗)), in six individuals from three Faroe Island PCD-affected families that all carried an 8.8 Mb shared haplotype across HYDIN, indicating an ancestral founder mutation in this isolated population. We demonstrate by electron microscopy tomography that, consistent with the effects of loss-of-function mutations, HYDIN mutant respiratory cilia lack the C2b projection of the central pair (CP) apparatus; similar findings were reported in Hydin-deficient Chlamydomonas and mice. High-speed videomicroscopy demonstrated markedly reduced beating amplitudes of respiratory cilia and stiff sperm flagella. Like the hy3 mouse model, all nine PCD-affected persons had normal body composition because nodal cilia function is apparently not dependent on the function of the CP apparatus.

An international registry for primary ciliary dyskinesia

“…While tremendous progress has been made in recent years in unveiling the molecular mechanisms of the disease [2,3,[8][9][10][11][12][13][14][15][16][17][18][19], PCD management is still hampered by a lack of fundamental data on epidemiology, clinical presentation, disease course and effects of different treatment strategies [4][5][6]. Patient registries are well-known tools to assemble sufficient numbers of individuals with a rare disease to assess and monitor patient data in a standardised and longitudinal way, and to recruit candidates for clinical research studies [20,21].…”

Genetic Disturbances in Patients with Bodily Isomerism from a Single Center: Clinical Implications of Affected Genes and Potential Impact of Ciliary Dyskinesia

“…Studies have shown that mutations in genes affecting the central pair of microtubules can cause laterality abnormalities while mutations in genes affecting portions of the cilia other than the central pair do not affect laterality. 65,66 It is not only flow of embryonic fluid created by this rotary movement of cilia that affects laterality, however, but also impairment in ciliary sensory function. While the motile nodal cilia create the leftward flow of embryonic fluid, there is the requirement of downstream cilia to sense the flow, thus producing the co-called two-cilia hypothesis.…”

Diagnostic Methods in Primary Ciliary Dyskinesia

“…For example, defects of nexin link components [63], central pair components [64], ciliary biogenesis defects [14] and defects caused by DNAH11 [65,66], usually cannot be visualized by classic TEM. Thus, normal ultrastructure cannot rule out PCD.…”

“…Male patients with mutations in CCDC114 (coding for a docking protein for the ODA) are generally fertile [70]. Situs abnormalities are not observed in patients with mutations affecting the central pair [64] or radial spokes [49,50,69], nor in patients with reduced generation of multiple motile cilia [13,14]. However, it is likely that variable clinical pictures occur between patients with different mutations within a particular gene and even between patients with identical mutations.…”