Mutations in radial spoke head genes and ultrastructural cilia defects in East-European cohort of primary ciliary dyskinesia patients
| Autor: | Hanna Dmenska, Ewa Ziętkiewicz, Michał Witt, Barbara Klimek, Katarzyna Voelkel, Zuzanna Bukowy-Bieryllo, Andrzej Pogorzelski, Anna Sulikowska-Rowińska, Ewa Rutkiewicz |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Heredity medicine.disease_cause Polymerase Chain Reaction Biochemistry Pediatrics Cohort Studies 0302 clinical medicine Europe Eastern Polymorphism Single-Stranded Conformational Primary ciliary dyskinesia Genetics 0303 health sciences Mutation education.field_of_study Multidisciplinary Radial spoke head Cilium Phenotype 3. Good health Pedigree Cytochemistry Medicine Female Research Article Science Population Single-nucleotide polymorphism Bronchi Biology Polymorphism Single Nucleotide 03 medical and health sciences medicine otorhinolaryngologic diseases Humans Cilia education 030304 developmental biology Clinical Genetics Kartagener Syndrome medicine.disease Situs inversus Cytoskeletal Proteins 030228 respiratory system Population Genetics |
| Zdroj: | PLoS ONE, Vol 7, Iss 3, p e33667 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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