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DNAI1
dynein axonemal intermediate chain 1
The DNAI1 gene provides instructions for a protein that forms a key component of dynein complexes, essential for the proper movement of cilia in various cells. DNAI1 encodes dynein axonemal intermediate chain 1, a protein critical for the assembly and function of outer dynein arms within cilia.
DNAI1 is located on the short (p) arm of chromosome 9, at band 9p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The DNAI1 gene, also known as dynein axonemal intermediate chain 1, plays a vital role in human biology by contributing to the structure and function of cilia. Cilia are microscopic, hair-like projections on the surface of many cells that are responsible for moving cells or fluids over cell surfaces.
Disruptions in DNAI1 can lead to dysfunctional cilia, impacting various bodily systems where ciliary movement is crucial, including the respiratory tract and reproductive system. Its inheritance pattern is autosomal recessive.
What the gene does
The DNAI1 gene provides instructions for synthesising an intermediate chain protein that is a part of the larger dynein protein complex. Dynein complexes are molecular motors located within cilia, specifically contributing to both inner and outer dynein arms. These arms generate the necessary force for cilia to bend and move in a coordinated fashion.
The protein produced from DNAI1 is specifically integrated into the outer dynein arms (ODAs) within the axoneme, which is the core structure of cilia. The synchronous beating of these dynein arms enables the cilia to propel fluids or move cells effectively. Without functional DNAI1 protein, the proper assembly and operation of these crucial ciliary structures are compromised, affecting motility.
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Chromosome location
The DNAI1 gene is situated on the short arm of chromosome 9 at position 9p13.3. This specific location indicates its chromosomal address within the human genome.
Protein structure
The DNAI1 protein consists of 699 amino acids. It features several distinct domains. At the N-terminus, there are two disordered regions, located at amino acids 1-54 and 140-170. The protein also contains seven WD repeats, which are predicted to form beta-propeller structures. These include WD 1 (amino acids 320-370), WD 2 (amino acids 375-413), WD 3 (amino acids 422-465), WD 4 (amino acids 474-526), WD 5 (amino acids 531-570), WD 6 (amino acids 574-612), and WD 7 (amino acids 618-658).
Key variants
Variants within the DNAI1 gene can lead to alterations in the protein's structure or function, impairing its ability to contribute to the dynein complex. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, all of which may result in a non-functional or improperly functioning protein. Such variants are associated with inherited conditions primarily affecting ciliary motility.
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.1319G>A | p.Trp440Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.139del | p.Ala47fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.155del | p.Pro52fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1643G>A | p.Trp548Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1644del | p.Ser547_Trp548insTer | Pathogenic | ★★☆☆ | Kartagener syndrome |
c.1653C>G | p.Tyr551Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1719-1G>A | - | Pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.194_196dup | p.Phe66Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.272dup | p.Tyr91Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.885_886dup | p.Asp296fs | Pathogenic | ★★☆☆ | Kartagener syndrome |
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 variants in the DNAI1 gene are primarily associated with inherited conditions that disrupt the normal function of cilia. The most notable condition linked to DNAI1 is Primary ciliary dyskinesia, an autosomal recessive disorder characterised by impaired ciliary movement. DNAI1 variants are also implicated in Heterotaxy syndrome.
- Primary ciliary dyskinesia Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic DNAI1 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
In the UK, the DNAI1 gene is assessed on several NHS Genomic Medicine Service national panels. It is included on panels for Foetal anomalies (R21), Laterality disorders and isomerism (R139), Primary ciliary disorders, and Respiratory ciliopathies including non-CF bronchiectasis (R189), all classified as 'green' for their clinical utility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the DNAI1 gene?
The DNAI1 gene provides instructions for making an intermediate chain protein that is an essential part of the dynein complex. This complex powers the movement of cilia, which are microscopic, hair-like structures on cell surfaces that move fluids or cells.
What condition is associated with variants in the DNAI1 gene?
Variants in the DNAI1 gene are primarily associated with Primary ciliary dyskinesia. This is an inherited disorder characterised by dysfunctional cilia, leading to issues predominantly affecting the respiratory system and fertility.
How is Primary ciliary dyskinesia inherited?
Primary ciliary dyskinesia associated with DNAI1 variants is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition. Carriers, with one altered copy, typically do not show symptoms.
References
- Ziętkiewicz E, Nitka B, Voelkel K. Population specificity of the DNAI1 gene mutation spectrum in primary ciliary dyskinesia (PCD). Respiratory research. 2010. PMID: 21143860
- Escudier E, Duquesnoy P, Papon JF. Ciliary defects and genetics of primary ciliary dyskinesia. Paediatric respiratory reviews. 2009. PMID: 19410201
- Leigh MW, Pittman JE, Carson JL. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genetics in medicine : official journal of the American College of Medical Genetics. 2009. PMID: 19606528
- Failly M, Saitta A, Muñoz A. DNAI1 mutations explain only 2% of primary ciliary dykinesia. Respiration; international review of thoracic diseases. 2008. PMID: 18434704
- Zariwala MA, Leigh MW, Ceppa F. Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. American journal of respiratory and critical care medicine. 2006. PMID: 16858015
- Pennarun G, Escudier E, Chapelin C. Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. American journal of human genetics. 1999. PMID: 10577904
- Adam MP, Bick S, Mirzaa GM. Primary Ciliary Dyskinesia. 1993. PMID: 20301301