Abstract
Primary ciliary dyskinesia (PCD) is a rare (1/20,000), multisystem disease with a complex phenotype caused by the impaired motility of cilia/flagella, usually related to ultrastructural defects of these organelles. Mutations in genes encoding radial spoke head (RSPH) proteins, elements of the ciliary ultrastructure, have been recently described. However, the relative involvement of RSPH genes in PCD pathogenesis remained unknown, due to a small number of PCD families examined for mutations in these genes. The purpose of this study was to estimate the involvement of RSPH4A and RSPH9 in PCD pathogenesis among East Europeans (West Slavs), and to shed more light on ultrastructural ciliary defects caused by mutations in these genes. The coding sequences of RSPH4A and RSPH9 were screened in PCD patients from 184 families, using single strand conformational polymorphism analysis and sequencing. Two previously described (Q109X; R490X) and two new RSPH4A mutations (W356X; IVS3_2–5del), in/around exons 1 and 3, were identified; no mutations were found in RSPH9. We estimate that mutations in RSPH4A, but not in RSPH9, are responsible for 2–3% of cases in the East European PCD population (4% in PCD families without situs inversus; 11% in families preselected for microtubular defects). Analysis of the SNP-haplotype background provided insight into the ancestry of repetitively found mutations (Q109X; R490X; IVS3_2–5del), but further studies involving other PCD cohorts are required to elucidate whether these mutations are specific for Slavic people or spread among other European populations. Ultrastructural defects associated with the mutations were analyzed in the transmission electron microscope images; almost half of the ciliary cross-sections examined in patients with RSPH4A mutations had the microtubule transposition phenotype (9+0 and 8+1 pattern). While microtubule transposition was a prevalent ultrastructural defect in cilia from patients with RSPH4A mutations, similar defects were also observed in PCD patients with mutations in other genes.
Highlights
Primary ciliary dyskinesia (PCD; MIM #242650) is a rare, multisystem disease with the prevalence of 1/20,000 [1]
PCD-causing mutations have been found in twelve genes, encoding proteins involved in the ciliary ultrastructure (DNAH11, DNAI2, DNAL1, TXNDC3, RSPH9, RSPH4A, CCDC39, CCDC40) or assembly (KTU, LRRC50) [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]; mutations in RPGR and OFD1 have been reported in rare syndromic forms of PCD [27,28,29,30]
The earlier report on mutations in RSPH4A and RSPH9 [19] has been based on a much smaller study group of seven PCD families preselected for the presence of MT defects, and included only a single European family
Summary
Primary ciliary dyskinesia (PCD; MIM #242650) is a rare, multisystem disease with the prevalence of 1/20,000 [1]. PCD-causing mutations have been found in twelve genes, encoding proteins involved in the ciliary ultrastructure (DNAH11, DNAI2, DNAL1, TXNDC3, RSPH9, RSPH4A, CCDC39, CCDC40) or assembly (KTU, LRRC50) [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]; mutations in RPGR and OFD1 have been reported in rare syndromic forms of PCD [27,28,29,30]. Mutations in CCDC39 and CCDC40 genes, encoding proteins involved in the formation of dynein regulatory complex, have been reported in a considerable number of PCD patients with defects in MT arrangement [24,26]. RSPH4A and RSPH9, both encoding radial spoke head proteins, are other genes reported to be mutated in PCD patients with MT defects [19]. Data on ultrastructural cilia defects in patients with RSPH defects remain scarce
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