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DNAH5
dynein axonemal heavy chain 5
The DNAH5 gene provides instructions for making a protein critical for the proper movement of cilia, microscopic structures involved in various bodily functions, and is associated with Primary Ciliary Dyskinesia. The DNAH5 gene encodes the dynein axonemal heavy chain 5 protein, an essential part of the cellular machinery enabling cilia to move.
DNAH5 is located on the short (p) arm of chromosome 5, at band 5p15.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The DNAH5 gene, or dynein axonemal heavy chain 5, is fundamental for the assembly and function of dynein complexes within cilia. Cilia are tiny, hair-like projections on the surface of many cell types, which play crucial roles in moving fluids and cells in various organ systems, including the respiratory and reproductive tracts. Variations in DNAH5 can disrupt these vital cellular processes, leading to specific health conditions.
What the gene does
The DNAH5 gene provides instructions for synthesising the dynein axonemal heavy chain 5 protein, a heavy chain subunit of the dynein complex. Dynein complexes are motor proteins that form inner and outer dynein arms within the axoneme, the core structure of motile cilia. These dynein arms generate the force required for the coordinated, rhythmic beating motion of cilia, which is essential for clearing mucus from airways, moving egg cells in the fallopian tubes, and facilitating sperm motility. Specifically, the DNAH5-encoded protein is a component of the outer dynein arms, which are vital for generating the powerful strokes of the cilia. Without functional DNAH5 protein, the dynein arms cannot assemble correctly or move efficiently, compromising ciliary function.
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Chromosome location
The DNAH5 gene is situated on the short arm of chromosome 5, specifically at position 5p15.2. This genomic location specifies where the gene resides within the human genome, providing a precise address for genetic studies and diagnostic investigations.
Protein structure
The DNAH5 protein is a large polypeptide chain, comprising 4624 amino acids. It features several distinct regions and coiled-coil domains essential for its function. The protein includes a large Stem region (amino acids 1-1941) and a Stalk region (amino acids 3185-3482). Key to its motor function are six AAA (ATPases Associated with various cellular Activities) domains, labelled AAA 1 (amino acids 1942-2164), AAA 2 (amino acids 2224-2443), AAA 3 (amino acids 2550-2803), AAA 4 (amino acids 2916-3170), AAA 5 (amino acids 3567-3797), and AAA 6 (amino acids 4012-4226). Additionally, various coiled-coil regions are distributed throughout the protein, including those at amino acids 284-305, 740-825, 1435-1465, 3195-3302, 3426-3491, 3732-3817, and 4392-4420.
Key variants
Genetic variations, or variants, within the DNAH5 gene can disrupt the production or function of the dynein axonemal heavy chain 5 protein. These variants are typically inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected. Such alterations can lead to impaired ciliary movement, underlying the pathology of associated conditions.
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.10399del | p.Gln3467fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.13096A>T | p.Lys4366Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1701del | p.Ala568fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1726G>T | p.Glu576Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.5527G>T | p.Glu1843Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.5556del | p.Asp1852fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia 3 |
c.5928del | p.Ala1977fs | Pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.7389del | p.Gly2464fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.7609+1_7609+3del | - | Pathogenic/Likely pathogenic | ★★☆☆ | DNAH5-related disorders |
c.817C>T | p.Gln273Ter | Pathogenic | ★★☆☆ | Respiratory ciliopathies including non-CF bronchiectasis |
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
Variants in the DNAH5 gene are predominantly linked to Primary Ciliary Dyskinesia (PCD), an inherited disorder characterised by defects in the structure and function of motile cilia. Individuals with PCD often experience recurrent respiratory tract infections, issues with fertility, and, in some cases, situs inversus, where internal organs are mirrored from their usual positions. Some research also indicates a potential association with Heterotaxy syndrome.
- Primary ciliary dyskinesia Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic DNAH5 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
The DNAH5 gene is recognised within the UK's NHS Genomic Medicine Service, featuring on several NHS England 'green' (evidence-based) gene panels. These include panels for Foetal anomalies (R21), Laterality disorders and isomerism (R139), Non-CF bronchiectasis, Primary ciliary disorders, and Respiratory ciliopathies including non-CF bronchiectasis (R189), as well as being listed in DDG2P (Developmental Disorders Genotype-Phenotype Database).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the DNAH5 gene?
The DNAH5 gene is responsible for producing a protein that is a crucial component of the dynein complex, which acts as a motor protein within cilia. This protein enables the coordinated, rhythmic beating motion of cilia, essential for various bodily functions like clearing airways.
How are variants in the DNAH5 gene typically inherited?
Variants in the DNAH5 gene are typically inherited in an autosomal recessive manner. This means that an individual must inherit two copies of a pathogenic variant, one from each parent, to develop a condition associated with this gene.
What health conditions are associated with DNAH5 gene variants?
Variants in the DNAH5 gene are primarily associated with Primary Ciliary Dyskinesia (PCD). This condition affects the movement of cilia, leading to symptoms such as recurrent respiratory infections and fertility issues.
References
- Djakow J, Svobodová T, Hrach K. Effectiveness of sequencing selected exons of DNAH5 and DNAI1 in diagnosis of primary ciliary dyskinesia. Pediatric pulmonology. 2012. PMID: 22416021
- Failly M, Bartoloni L, Letourneau A. Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia. Journal of medical genetics. 2009. PMID: 19357118
- 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
- Hornef N, Olbrich H, Horvath J. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. American journal of respiratory and critical care medicine. 2006. PMID: 16627867
- Olbrich H, Häffner K, Kispert A. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nature genetics. 2002. PMID: 11788826
- Adam MP, Bick S, Mirzaa GM. Primary Ciliary Dyskinesia. 1993. PMID: 20301301