rs397515563 — DNAI1 DNAI1 IVS19+1G>A

DNAI1 IVS19+1G>A — Carrier Status for a Rare Ciliary Motor Disorder

Cilia are microscopic hair-like projections that line virtually every airway in your respiratory tract, propelling mucus and trapped particles upward and out of your lungs. The engine that drives ciliary beating is the outer dynein arm¹¹ outer dynein arm
a multi-protein motor complex attached to the outer doublet microtubules of the ciliary axoneme; it converts ATP into the mechanical force that drives ciliary movement — and DNAI1 encodes one of its essential structural components (the intermediate chain IC78/DNAI1). When both copies of DNAI1 are non-functional, cilia stop beating normally, mucus accumulates in the airways, and the condition known as primary ciliary dyskinesia (PCD) results.

rs397515563 (also written IVS19+1G>A or c.2001+1G>A) disrupts the canonical splice donor GT dinucleotide²² canonical splice donor GT dinucleotide
the invariant GT at the +1 position of an intron splice donor site is required for the spliceosome to recognize and excise the intron; changing it abolishes normal splicing at the start of intron 19. The result is that exon 19 is skipped entirely during mRNA processing, producing a protein with 61 amino acids deleted (A607_K667del). This deleted region falls within a functional domain of the outer dynein arm intermediate chain, and the truncated protein cannot support normal ciliary structure.

The Mechanism

DNAI1 (dynein axonemal intermediate chain 1) is a 699-amino-acid protein that forms part of the outer dynein arm (ODA) — the molecular motor unit attached at regular intervals along the outer doublet microtubules of the ciliary axoneme. The ODA generates the sliding force between microtubule doublets that produces ciliary beating. When either ODA motor protein subunit is absent or non-functional, cilia either cannot beat or beat in abnormal, uncoordinated patterns that fail to generate net airway flow.

The IVS19+1G>A substitution changes the invariant G at position +1 of intron 19 to an A. This single nucleotide change abolishes the canonical GT splice donor sequence recognized by the U1 snRNA component of the spliceosome. In vitro splicing assays confirmed³³ In vitro splicing assays confirmed
performed by Zariwala et al. using patient cDNA and minigene constructs; the assay directly demonstrated exon 19 skipping in the presence of the IVS19+1G>A mutation that the mutant allele produces a shortened mRNA lacking exon 19, which is translated into a DNAI1 protein missing residues A607 through K667. The resulting protein cannot properly integrate into outer dynein arm complexes.

Because PCD is autosomal recessive, one functional DNAI1 copy is sufficient for normal ciliary structure and function. Carriers of a single IVS19+1G>A allele paired with a normal allele produce enough wild-type DNAI1 protein from their unaffected chromosome and have completely normal mucociliary clearance with no respiratory symptoms attributable to this variant.

The Evidence

Zariwala et al. 2006⁴⁴ Zariwala et al. 2006
American Journal of Respiratory and Critical Care Medicine; 179 unrelated PCD families identified the IVS19+1G>A mutation in a patient with PCD who carried it in trans with the founder IVS1+2_3insT mutation. The study found DNAI1 mutations in 9% of families overall and confirmed via in vitro splicing assay that IVS19+1G>A produces exon 19 skipping and the in-frame deletion of 61 amino acids (A607_K667del). When considering only families with outer dynein arm (ODA) defects on electron microscopy — the ultrastructural hallmark of DNAI1 mutations — the frequency rises to 13–14%.

Guichard et al. 2001⁵⁵ Guichard et al. 2001
American Journal of Human Genetics; 34 PCD patients established that compound heterozygosity in DNAI1 produces both Kartagener syndrome (PCD with situs inversus) and PCD without organ reversal. The randomization of left-right body asymmetry in PCD occurs because embryonic nodal cilia — the left-right organizer — depend on the same dynein arm machinery; ODA defects disrupt directional nodal flow, leading to ~50% chance of situs inversus.

Ziétkiewicz et al. 2010⁶⁶ Ziétkiewicz et al. 2010
Respiratory Research; 157 Polish PCD families examined population specificity of DNAI1 mutations and confirmed that DNAI1 accounts for 7–10% of worldwide PCD, with the IVS1+2-3insT founder mutation comprising ~54% of all identified DNAI1 pathogenic alleles globally. The IVS19+1G>A variant is one of the rarer DNAI1 mutations, observed at an allele frequency of approximately 0.000002 in gnomAD exomes.

For disease management, PCD Foundation consensus recommendations⁷⁷ PCD Foundation consensus recommendations
Shapiro et al. 2016; expert panel covering airway clearance, surveillance culture protocols, antibiotic regimens, ENT care, and fertility provide the current clinical standard of care. An emerging therapeutic approach — inhaled DNAI1 mRNA lipid nanoparticle therapy⁸⁸ inhaled DNAI1 mRNA lipid nanoparticle therapy
Hennig et al. 2025 (PNAS); preclinical study demonstrating protein production in NHP airways and functional rescue in PCD cell models at therapeutic doses — has shown preclinical promise for gene-specific restoration of ciliary function.

Practical Implications

Carriers (one IVS19+1G>A allele, one normal allele) are completely unaffected. No respiratory symptoms, no hearing issues, no laterality defects. The only practical relevance for a carrier is reproductive: if both partners in a couple carry pathogenic DNAI1 variants (on different alleles), each pregnancy carries a 25% risk of producing an affected child with PCD. Genetic counseling and partner testing are the key actions.

For affected individuals with PCD (biallelic DNAI1 mutations): management is coordinated through respiratory medicine, ENT, audiology, and (for males) andrology. Airway clearance therapy is the cornerstone. Nearly 100% of males with PCD are infertile due to sperm flagellar immotility from the same ODA defect — but assisted reproductive techniques, particularly ICSI, achieve successful fertilization because sperm vitality (DNA integrity) is preserved even when motility is absent.

Interactions

PCD is genetically heterogeneous — over 50 genes encoding axonemal components can cause the condition when both copies are disrupted. The most common DNAI1 pathogenic allele (IVS1+2-3insT, the founder mutation accounting for ~54% of DNAI1 alleles worldwide) can pair with IVS19+1G>A in compound heterozygosity to produce full PCD. DNAH5 (outer dynein arm heavy chain) and DNAAF1 (dynein axonemal assembly factor 1) are among the other ODA genes; loss-of-function variants in any of these can combine with DNAI1 variants only within the same gene (compound heterozygosity within DNAI1 is required for disease — heterozygosity for DNAI1 + DNAH5 does not produce PCD because different subunits complement each other).