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DNAH5
dynein axonemal heavy chain 5
The DNAH5 gene provides instructions for a protein that is a crucial component of dynein, a molecular motor complex responsible for the movement of cilia in various tissues. DNAH5 encodes the dynein axonemal heavy chain 5 protein, which is vital for the proper function of cilia.
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, also known as dynein axonemal heavy chain 5, plays a fundamental role in the assembly and function of cilia. Cilia are tiny, finger-like projections found on the surface of many cell types throughout the body, including those lining the respiratory and reproductive systems. The coordinated beating of cilia is essential for moving fluids and cells, such as clearing mucus from the lungs or facilitating the movement of gametes.
DNAH5 produces a specific component of the dynein complex, which acts as a motor protein within cilia, generating the force required for their movement. Disruptions to this gene can impair ciliary function, leading to various health conditions, most notably primary ciliary dyskinesia.
What the gene does
The DNAH5 gene provides the blueprint for the dynein axonemal heavy chain 5 protein, a critical subunit of the dynein complex. Dynein is a major motor protein within cilia, which are microscopic, hair-like structures present on the surface of many cells. These cilia perform essential functions, such as clearing debris from the respiratory tract and facilitating the transport of reproductive cells.
Within the core of cilia, known as the axoneme, dynein forms structures called inner dynein arms (IDAs) and outer dynein arms (ODAs). These arms are responsible for producing the mechanical force that drives the bending and movement of cilia. The DNAH5 protein is specifically found in the outer dynein arms, where it contributes to the generation of the power stroke necessary for effective ciliary beating. Without a functional DNAH5 protein, the dynein complex cannot assemble correctly, leading to impaired ciliary motility.
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Chromosome location
The DNAH5 gene is situated on the short arm of chromosome 5, specifically at position 5p15.2. This location indicates its precise address within the human genome. The gene's position is important for understanding its genetic context and how it might be inherited or involved in chromosomal rearrangements.
Protein structure
The DNAH5 protein is a large polypeptide comprising 4624 amino acids. Its structure includes several key functional regions. The N-terminal region is characterised by a long Stem, spanning amino acids 1-1941, which incorporates multiple Coiled coil motifs at positions 284-305, 740-825, and 1435-1465. Following this, the protein contains six AAA (ATPases Associated with various cellular Activities) domains, critical for its motor function: AAA 1 (1942-2164), AAA 2 (2224-2443), AAA 3 (2550-2803), AAA 4 (2916-3170), AAA 5 (3567-3797), and AAA 6 (4012-4226). Interspersed within these domains and towards the C-terminus are additional structural elements, including a Stalk region (3185-3482) containing Coiled coil motifs (3195-3302 and 3426-3491), and a further Coiled coil region at 3732-3817 and 4392-4420.
Key variants
Genetic variants in the DNAH5 gene can impact the production or function of the dynein axonemal heavy chain 5 protein. These changes can range from single nucleotide alterations to larger deletions or insertions within the gene sequence. Pathogenic variants typically disrupt the protein's ability to assemble correctly or function within the ciliary dynein complex, leading to impaired ciliary movement.
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.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.817C>T | p.Gln273Ter | Pathogenic | ★★☆☆ | Respiratory ciliopathies including non-CF bronchiectasis |
c.870G>A | p.Trp290Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.9272dup | p.Glu3093fs | 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
Variants in the DNAH5 gene are primarily associated with inherited conditions that affect ciliary function. The most well-characterised condition linked to DNAH5 variants is Primary ciliary dyskinesia. This condition is characterised by chronic respiratory tract infections, issues with fertility, and in some cases, situs inversus, where internal organs are positioned on the opposite side of the body.
- 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 well-recognised within the UK's genomic healthcare system. It is listed on several green-lighted panels in NHS England's PanelApp, indicating strong evidence for its association with disease. These include panels for DDG2P, Foetal anomalies (R21), Laterality disorders and isomerism (R139), Non-CF bronchiectasis, Primary ciliary disorders, and Respiratory ciliopathies including non-CF bronchiectasis (R189).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What are cilia and why are they important?
Cilia are tiny, hair-like projections extending from the surface of many cells. They are crucial for moving fluids and particles across cell surfaces, such as clearing mucus from the lungs, moving eggs through fallopian tubes, and facilitating fluid flow in other organ systems.
What is primary ciliary dyskinesia (PCD)?
Primary ciliary dyskinesia (PCD) is an inherited disorder characterised by defects in the structure or function of cilia. This leads to impaired ciliary movement, resulting in chronic respiratory infections, fertility issues, and sometimes situs inversus (reverse organ placement).
How is DNAH5 inherited?
DNAH5-related conditions, such as primary ciliary dyskinesia, are typically inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene (one from each parent) to develop the condition.
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