<i>DNAI1</i> Mutations Explain Only 2% of Primary Ciliary Dykinesia

Abstract

Background: Primary ciliary dyskinesia (PCD) is a rare recessive hereditary disorder characterized by dysmotility to immotility of ciliated and flagellated structures. Its main symptoms are respiratory, caused by defective ciliary beating in the epithelium of the upper airways (nose, bronchi and paranasal sinuses). Impairing the drainage of inhaled microorganisms and particles leads to recurrent infections and pulmonary complications. To date, 5 genes encoding 3 dynein protein arm subunits (DNAI1, DNAH5 and DNAH11), the kinase TXNDC3 and the X-linked RPGR have been found to be mutated in PCD. Objectives: We proposed to determine the impact of the DNAI1 gene on a cohort of unrelated PCD patients (n = 104) recruited without any phenotypic preselection. Methods: We used denaturing high-performance liquid chromatography and sequencing to screen for mutations in the coding and splicing site sequences of the gene DNAI1. Results: Three mutations were identified: a novel missense variant (p.Glu174Lys) was found in 1 patient and 2 previously reported variants were identified (p.Trp568Ser in 1 patient and IVS1+2_3insT in 3 patients). Overall, mutations on both alleles of gene DNAI1 were identified in only 2% of our clinically heterogeneous cohort of patients. Conclusion: We conclude that DNAI1 gene mutation is not a common cause of PCD, and that major or several additional disease gene(s) still remain to be identified before a sensitive molecular diagnostic test can be developed for PCD.

Normal live birth after testicular sperm extraction and intracytoplasmic sperm injection in variant primary ciliary dyskinesia with completely immotile sperm and structurally abnormal sperm tails

“…The causal mutation in >50% of PCD cases remains unknown. Of the known causes, DNAI1 (2%) and DNAH5 (15%) constitute the largest proportions (4,(20)(21)(22). In all of the above cases, sperm structure at a light-microscopic level appears normal, but EM studies revealed only axonemal defects; in contrast, it is important to note that the dynein arms, nexin linkages and radial spokes were normal in this man and that the different defects in sperm structure suggested that studies of the above genes were unlikely to be valuable.…”

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children

“…Respiratory cilia were either immotile or showed some residual flickery movement. [17,[37][38][39][40]. This gene was identified based on a candidate gene approach since Chlamydomonas algae lacking IC78 lost 70% of their motility and were slow swimming [17,41].…”

Mutations ofDNAH11in patients with primary ciliary dyskinesia with normal ciliary ultrastructure

“…Genetic testing holds promise as a diagnostic approach in patients with a clinical phenotype compatible with PCD, as approximately 50% of PCD can be accounted for by biallelic mutations in 12 genes 5–23. Mutations in two genes; dynein axonemal intermediate chain 1 ( DNAI1 ), and dynein axonemal heavy chain 5 ( DNAH5 ), that code for ciliary outer dynein arm (ODA) proteins are the most common genetic causes of PCD (18–30% of PCD),9 10 13 14 and mutations in the remaining genes are relatively uncommon.…”