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DYNC2H1
dynein cytoplasmic 2 heavy chain 1
The DYNC2H1 gene provides instructions for a key protein involved in the transport of materials within cilia, cellular structures crucial for development. DYNC2H1 encodes a heavy chain component of the dynein-2 protein complex, which plays a critical role in intraflagellar transport within cilia.
DYNC2H1 is located on the long (q) arm of chromosome 11, at band 11q22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The DYNC2H1 gene, located on chromosome 11, produces a protein that is an integral part of the dynein-2 complex. This complex is fundamental to the proper functioning of cilia, which are microscopic, finger-like projections on the surface of many cells.
Cilia are involved in various cellular signalling pathways, including those vital for the proliferation and differentiation of cells that form cartilage and bone. Understanding DYNC2H1 is important for comprehending conditions linked to ciliary dysfunction and skeletal development.
What the gene does
The protein encoded by DYNC2H1 is a heavy chain component of the dynein-2 complex, which is found within cilia. This complex facilitates intraflagellar transport (IFT), a process where materials are moved along the length of cilia. Specifically, the dynein-2 protein acts as a motor, utilising energy from ATP to transport cargo from the tip of the cilia back towards the base.
IFT is essential for both the assembly and maintenance of cilia. These cellular structures are critical for numerous chemical signalling pathways, including the Sonic Hedgehog pathway, which is important for cell growth, division, and maturation. The Sonic Hedgehog pathway is particularly vital for the development and specialisation of cartilage and bone cells.
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Chromosome location
The DYNC2H1 gene is situated on chromosome 11, specifically at band 11q22.3. This genomic location provides the blueprint for the dynein cytoplasmic 2 heavy chain 1 protein.
Protein structure
The DYNC2H1 protein is a large protein, composed of 4307 amino acids. Its structure includes several distinct regions. The N-terminal portion comprises a Stem region (amino acids 1-1650), which includes a Coiled coil segment (amino acids 1074-1103). Following this are six AAA domains: AAA 1 (amino acids 1651-1875), AAA 2 (amino acids 1938-2161), AAA 3 (amino acids 2251-2505), AAA 4 (amino acids 2617-2863), AAA 5 (amino acids 3244-3473), and AAA 6 (amino acids 3690-3905). A Stalk region (amino acids 2881-3169) contains two Coiled coil segments (amino acids 2897-2982 and 3109-3200). Another Coiled coil segment is also present within the AAA 5 domain (amino acids 3408-3442).
Key variants
Variants in the DYNC2H1 gene can alter the function of the dynein-2 complex, affecting intraflagellar transport and ciliary function. Over 50 different pathogenic variants have been identified, primarily missense changes that alter single amino acids in the protein. These changes can lead to a spectrum of ciliary disorders, particularly those affecting skeletal development.
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.10112C>G | p.Ser3371Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Asphyxiating thoracic dystrophy 3 |
c.10342C>T | p.Gln3448Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Jeune thoracic dystrophy |
c.11565dup | p.Asp3856fs | Pathogenic/Likely pathogenic | ★★☆☆ | Asphyxiating thoracic dystrophy 3 |
c.1243C>T | p.Gln415Ter | Pathogenic | ★★☆☆ | Jeune thoracic dystrophy |
c.3859C>T | p.Arg1287Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Asphyxiating thoracic dystrophy 3 |
c.4877G>A | p.Trp1626Ter | Pathogenic | ★★☆☆ | Asphyxiating thoracic dystrophy 3 |
c.5643_5646del | p.Arg1881fs | Pathogenic/Likely pathogenic | ★★☆☆ | Asphyxiating thoracic dystrophy 3 |
c.6448G>T | p.Glu2150Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Asphyxiating thoracic dystrophy 3 |
c.6649C>T | p.Arg2217Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Jeune thoracic dystrophy |
c.7284T>A | p.Cys2428Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Asphyxiating thoracic dystrophy 3 |
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 DYNC2H1 gene are associated with several inherited conditions, primarily affecting bone growth. These include Jeune asphyxiating thoracic dystrophy, characterised by a small chest, short ribs, and shortened limb bones. DYNC2H1 variants are thought to account for a significant proportion of cases of this condition. Additionally, mutations in DYNC2H1 are linked to types of short-rib polydactyly syndromes, which share similar features with asphyxiating thoracic dystrophy.
- Jeune asphyxiating thoracic dystrophy
- Short-rib polydactyly syndromes Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic DYNC2H1 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 DYNC2H1 gene is recognised in the UK by NHS England's National Genomic Test Directory. It is included on several PanelApp panels, including Clefting, DDG2P, Foetal anomalies (R21), Rare multisystem ciliopathy disorders, Renal ciliopathies, Retinal disorders (R32), Skeletal ciliopathies, Skeletal dysplasia (R104), and Thoracic dystrophies. This inclusion highlights its clinical significance in diagnosing a range of inherited conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the DYNC2H1 gene?
The DYNC2H1 gene provides instructions for a protein that is a crucial component of the dynein-2 complex, responsible for transporting materials within cilia. This process, called intraflagellar transport, is essential for the proper assembly and maintenance of cilia.
What conditions are associated with DYNC2H1 gene variants?
Pathogenic variants in the DYNC2H1 gene are associated with inherited skeletal disorders, including Jeune asphyxiating thoracic dystrophy and various forms of short-rib polydactyly syndromes. These conditions affect bone growth and development.
How does DYNC2H1 relate to cilia?
The protein produced by DYNC2H1 is an essential motor protein within cilia. It powers the movement of substances from the tip to the base of cilia, a process vital for cilia's role in cell signalling and proper development.
References
- Okamoto T, Nagaya K, Kawata Y. Novel compound heterozygous mutations in DYNC2H1 in a patient with severe short-rib polydactyly syndrome type III phenotype. Congenital anomalies. 2015. PMID: 25410398
- Schmidts M, Arts HH, Bongers EM. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. Journal of medical genetics. 2013. PMID: 23456818
- El Hokayem J, Huber C, Couvé A. NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases. Journal of medical genetics. 2012. PMID: 22499340
- Merrill AE, Merriman B, Farrington-Rock C. Ciliary abnormalities due to defects in the retrograde transport protein DYNC2H1 in short-rib polydactyly syndrome. American journal of human genetics. 2009. PMID: 19361615
- Dagoneau N, Goulet M, Geneviève D. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. American journal of human genetics. 2009. PMID: 19442771