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PMID: 22448264 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mutations in radial spoke head genes and ultrastructural cilia defects in East-European cohort of primary ciliary dyskinesia patients.

PloS one ·Vol. 7 ·No. 3 ·2012-00-00 ·Pages e33667

Ziętkiewicz E, Bukowy-Bieryłło Z, Voelkel K, Klimek B, Dmeńska H, Pogorzelski A, Sulikowska-Rowińska A, Rutkiewicz E, Witt M

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.

MeSH Terms
Bronchi/pathology,ultrastructure Cilia/genetics,pathology,ultrastructure Cohort Studies Cytoskeletal Proteins/genetics Europe, Eastern Female Humans Kartagener Syndrome/genetics Male Mutation/genetics Pedigree Phenotype Polymerase Chain Reaction Polymorphism, Single Nucleotide/genetics Polymorphism, Single-Stranded Conformational
Chemicals
Cytoskeletal Proteins RSPH9 protein, human
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Ziętkiewicz Ewa
Department of Molecular and Clinical Genetics, Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland. [email protected]
Bukowy-Bieryłło Zuzanna
Voelkel Katarzyna
Klimek Barbara
Dmeńska Hanna
Pogorzelski Andrzej
Sulikowska-Rowińska Anna
Rutkiewicz Ewa
Witt Michał
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0033667
Email
[email protected]
Published
2012-00-00
Epub
2012-00-20
Pages
e33667
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3308995
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0033667 PMC Full Text View journal details
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