Population specificity of the DNAI1 gene mutation spectrum in primary ciliary dyskinesia (PCD)

Ewa Ziętkiewicz,Andrzej Pogorzelski,Barbara Nitka,Katarzyna Voelkel,Urszula Skrzypczak,Hanna Przystałowska,Zuzanna Bukowy,Ewa Rutkiewicz,Michał Witt,Kinga Humińska

doi:10.1186/1465-9921-11-174

Abstract

BackgroundMutations in the DNAI1 gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000. The estimates of the DNAI1 involvement in PCD pathogenesis differ among the reported studies, ranging from 4% to 10%.MethodsThe coding sequence of DNAI1 was screened (SSCP analysis and direct sequencing) in a group of PCD patients (157 families, 185 affected individuals), the first ever studied large cohort of PCD patients of Slavic origin (mostly Polish); multiplex ligation-dependent probe amplification (MLPA) analysis was performed in a subset of ~80 families.ResultsThree previously reported mutations (IVS1+2-3insT, L513P and A538T) and two novel missense substitutions (C388Y and G515S) were identified in 12 families (i.e. ~8% of non-related Polish PCD patients). The structure of background SNP haplotypes indicated common origin of each of the two most frequent mutations, IVS1+2-3insT and A538T. MLPA analysis did not reveal any significant differences between patients and control samples. The Polish cohort was compared with all the previously studied PCD groups (a total of 487 families): IVS1+2-3insT remained the most prevalent pathogenetic change in DNAI1 (54% of the mutations identified worldwide), and the increased global prevalence of A538T (14%) was due to the contribution of the Polish cohort.ConclusionsThe worldwide involvement of DNAI1 mutations in PCD pathogenesis in families not preselected for ODA defects ranges from 7 to 10%; this global estimate as well as the mutation profile differs in specific populations. Analysis of the background SNP haplotypes suggests that the increased frequency of chromosomes carrying A538T mutations in Polish patients may reflects local (Polish or Slavic) founder effect. Results of the MLPA analysis indicate that no large exonic deletions are involved in PCD pathogenesis.

Highlights

Mutations in the DNAI1 gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000
Primary ciliary dyskinesia (PCD; MIM #242650) is a multisystem disease characterized by recurrent respiratory tract infections, sinusitis, bronchiectasis and male sub-fertility; in about half of patients it is associated with situs inversus (Kartagener syndrome, KS; MIM #244400), resulting from the randomization of body symmetry
Characteristics of the detected variants SSCP screening of the entire coding region of DNAI1 was performed in patients from 108 PCD families; systematic search for mutations was not executed in twenty-one families where the segregation of the SNP haplotype was inconsistent with that of the disease, as well as in twenty-eight families where mutations were identified in other PCD-related genes [EZ, unpublished data]

Summary

Introduction

Mutations in the DNAI1 gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000. Among several genes confirmed to be directly involved in PCD pathogenesis, the major number of mutations were found in just two: DNAI1 (9p13.3) and DNAH5 (5p15.2), encoding intermediate and heavy chains of the axonemal dynein, respectively [13,14,15,16,17,18,19,20,21]. Mutations in other genes, coding for proteins involved in the axonemal ultrastructure (DNAH11, DNAI2, TXNDC3, RSPH9, RSPH4A) or assembly (KTU, CRRC50), were reported in singular PCD families only, and mutations in the RPGR gene were reported in rare cases of PCD associated with the X-linked retinitis pigmentosa Population specificity of DNAI1 mutation spectra is discussed in light of the SNP haplotype background of the mutations

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Conclusion