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

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.

Effectiveness of sequencing selected exons of DNAH5 and DNAI1 in diagnosis of primary ciliary dyskinesia

“…Zariwala et al8 described that it is a common mutation caused by founder effect. High proportion of this mutation in all the DNAI1 mutations was found also in the Polish10 and the Swiss11 populations. Most of the patients with DNAI1 mutations have at least one IVS1+2_3insT mutation.…”

“…Mutations in the DNAH5 gene are responsible for approximately 15–24% of all PCD cases 5–7. The second to DNAH5 in frequency is the DNAI1 (encoding the intermediate chain of ODAs), responsible for about 10% of the PCD cases,8–10 although a lower occurrence was also described 11. Other so far known genes mutated in the PCD include the RSPH9 , RSPH4A ,12 DNAH11 ,13 DNAI2 ,14 RPGR ,4 TXNDC3 ,15 KTU/PF13 ,16 LRRC50 ,17 CCDC39 ,18 and CCDC40 19…”

Embryonic development of the emu, Dromaius novaehollandiae

“…Compound heterozygosity for DNAI1 mutations was found in a patient with a normal ultrastructure of cilia (patient 22‐I). All the previously described PCD patients carrying DNAI1 mutations8–11 had ODA defects. We therefore asked a foreign histologist from a PCD diagnostic center to reassess the former TEM images of this patient and he evaluated them also as normal.…”

“…The selection of exons for the first step of testing was based on literature search on published DNAI1 and DNAH5 mutations 5–8, 10, 11, 20, 21. In the DNAH5 gene, the previously described five hot‐spot exons (34, 50, 63, 76, and 77) and additional four exons mutated in more than one unrelated families (33, 36, 48, and 49) were chosen.…”

An effective combination of sanger and next generation sequencing in diagnostics of primary ciliary dyskinesia

“…Mutations in the DNAH5 gene are responsible for approximately 15–24% of all PCD cases . The second most frequently involved gene has been so far the DNAI1 (encoding the intermediate chain of outer dynein arms), responsible for about 10% of the PCD cases, although not universally . More than 20 other genes have been reported to cause a limited number of PCD cases, often with distinct phenotypic characteristics (such as combined outer and inner dynein arm defects, central pair defects etc.).…”