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DNAI2
dynein axonemal intermediate chain 2
DNAI2 is located on the long (q) arm of chromosome 17, at band 17q25.1. Arm ratio per GRCh38 - banding schematic.
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Overview
DNAI2 is located on chromosome 17 and encodes dynein axonemal intermediate chain 2, a structural component of the dynein motor apparatus found in motile cilia. Cilia are slender, whip-like structures that extend from the surface of many cell types and generate rhythmic beating motions. In the respiratory tract, coordinated ciliary beating clears mucus and trapped particles from the airways, whilst during embryonic development ciliary motion helps establish the left-right body axis.
Pathogenic variants in DNAI2 disrupt the assembly or function of axonemal dynein complexes, leading to impaired ciliary movement. This can result in primary ciliary dyskinesia, a condition characterised by chronic respiratory infections, bronchiectasis, and in some cases abnormal organ positioning. Understanding DNAI2 is important for diagnosing ciliopathies and managing affected individuals through respiratory physiotherapy and infection surveillance.
What the gene does
The DNAI2 protein serves as an intermediate chain within the outer dynein arm, a multi-subunit protein complex attached to the microtubule doublets that form the structural backbone of cilia and flagella. Dynein arms convert chemical energy from ATP hydrolysis into mechanical force, causing microtubule doublets to slide past one another and thereby generating the bending motions that produce ciliary beating.
Within the dynein complex, intermediate chains such as DNAI2 play a structural role, linking the heavy chains that possess motor activity to the light chains and helping anchor the entire assembly to the ciliary axoneme. The protein contains multiple WD repeat domains, which typically fold into a beta-propeller structure that mediates protein-protein interactions. These repeats enable DNAI2 to scaffold other dynein components and ensure proper assembly of functional dynein arms during ciliogenesis.
When DNAI2 is absent or defective, outer dynein arms fail to assemble correctly onto ciliary microtubules, resulting in immotile or dyskinetic cilia. In the respiratory epithelium, this impairs mucociliary clearance, leading to mucus accumulation and recurrent infection. During embryogenesis, disrupted nodal cilia function can randomise left-right body patterning, occasionally resulting in situs inversus or heterotaxy.
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Chromosome location
DNAI2 is located on the long arm of chromosome 17 at band 17q25.1. This chromosomal region contains several genes involved in diverse cellular functions. The DNAI2 transcript encodes a protein of 605 amino acids, and the gene spans multiple exons that are spliced together during mRNA processing to produce the mature transcript.
Protein structure
The DNAI2 protein comprises 605 amino acids and features a distinctive arrangement of WD repeat domains. Five WD repeats are present: WD 1 (amino acids 150-203), WD 2 (amino acids 208-246), WD 3 (amino acids 253-294), WD 4 (amino acids 301-347), and WD 5 (amino acids 355-393), with additional WD 5 repeats at amino acids 399-437 and 443-481. These repeats typically assemble into a circular beta-propeller fold that provides a platform for binding partner proteins within the dynein complex. The protein also contains a disordered region spanning amino acids 568-605 at its C-terminus, which may confer flexibility for interactions with other dynein subunits or regulatory factors.
Key variants
Pathogenic variants in DNAI2 are typically loss-of-function changes that prevent normal dynein arm assembly. Both missense variants affecting critical residues within the WD repeat domains and truncating variants that result in absent or unstable protein have been reported. The inheritance pattern is autosomal recessive, meaning affected individuals carry pathogenic variants on both copies of the gene. Carrier individuals with one pathogenic variant generally do not show symptoms.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1122del | p.Phe375fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1173G>A | p.Trp391Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1326C>A | p.Cys442Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia 9 |
c.132del | p.Asn45fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1494+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.231dup | p.Glu78fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.562C>T | p.Gln188Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.739C>T | p.Arg247Ter | Pathogenic | ★★☆☆ | Primary ciliary dyskinesia 9 |
c.740G>A | p.Arg247Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia 9 |
c.873G>A | p.Trp291Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic DNAI2 variants are associated with primary ciliary dyskinesia, a genetically heterogeneous disorder characterised by chronic respiratory tract infections, bronchiectasis, and impaired mucociliary clearance. Some affected individuals also present with situs inversus or other laterality defects due to abnormal left-right patterning during embryonic development. The severity and specific manifestations can vary among individuals, reflecting differences in residual dynein function and potential modifier genes. Early diagnosis supports proactive airway clearance strategies and antimicrobial management to preserve lung function.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DNAI2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
DNAI2 is included on several NHS Genomic Medicine Service gene panels reflecting its role in ciliary disorders and developmental anomalies. It appears as a green-rated (high evidence) gene on the Fetal Anomalies panel (R21), the Laterality Disorders and Isomerism panel (R139), the Primary Ciliary Disorders panel, and the Respiratory Ciliopathies Including Non-CF Bronchiectasis panel (R189). Green classification indicates robust evidence supporting the gene-disease relationship, and variants in DNAI2 may be reported in diagnostic genomic testing for individuals with relevant clinical features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a DNAI2 variant?
Carriers have one pathogenic variant in DNAI2 and one working copy of the gene. They typically do not develop symptoms because the functional copy produces sufficient protein for normal ciliary function. Carrier status becomes relevant for family planning, as two carrier parents have a 25% chance with each pregnancy of having a child with two pathogenic variants who may develop primary ciliary dyskinesia.
How is primary ciliary dyskinesia related to DNAI2 diagnosed?
Diagnosis typically involves clinical assessment of respiratory symptoms, imaging to detect bronchiectasis, and specialised tests such as nasal nitric oxide measurement or analysis of ciliary beating patterns from nasal brushings. Genetic testing can confirm the diagnosis by identifying biallelic pathogenic variants in DNAI2 or other ciliary genes.
Can DNAI2 variants affect fertility?
Because dynein motors are also essential for sperm tail (flagellar) movement, some males with primary ciliary dyskinesia due to dynein gene variants experience reduced fertility. However, the impact varies depending on the specific variant and residual dynein function, and not all affected individuals have impaired fertility.