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DYNC2H1
dynein cytoplasmic 2 heavy chain 1
The DYNC2H1 gene provides instructions for a key protein involved in cilia function and intraflagellar transport, essential for cell signalling and skeletal development. DYNC2H1 is crucial for the proper formation and maintenance of cilia, which are microscopic, finger-like projections on cell surfaces.
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, or dynein cytoplasmic 2 heavy chain 1, encodes a protein that is a vital component of the dynein-2 protein complex. This complex plays a central role in the function of cilia, which are microscopic, hair-like structures found on the surface of many cell types. Proper cilia function is fundamental for various cellular processes, including critical signalling pathways that influence growth and development.
Mutations in the DYNC2H1 gene are associated with inherited disorders characterised by abnormal bone growth, collectively known as skeletal ciliopathies. These conditions often affect the skeleton, particularly the ribs and limbs.
What the gene does
The protein produced from the DYNC2H1 gene is an integral part of the dynein-2 complex, located within cellular structures called cilia. Cilia are crucial for cell-to-cell communication and various developmental processes. The dynein-2 complex is specifically involved in intraflagellar transport (IFT), a process responsible for moving materials along the length of cilia.
Acting as a molecular motor, the dynein-2 protein uses energy from ATP to facilitate the transport of molecules from the tip to the base of cilia. This transport mechanism is essential for both the assembly and ongoing maintenance of functional cilia. Cilia are involved in numerous signalling pathways, including the Sonic Hedgehog pathway, which is particularly important for the proliferation and differentiation of cells that form cartilage and bone.
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Chromosome location
The DYNC2H1 gene is situated on chromosome 11, specifically at position 11q22.3. This chromosomal location indicates its precise address within the human genome. Genes at this locus are transcribed and translated to produce their respective proteins, contributing to various biological functions.
Protein structure
The DYNC2H1 protein is a large molecule, comprising 4307 amino acids. Its structure includes several key functional domains. At the N-terminus, there is a Stem region spanning amino acids 1-1650, which contains a Coiled coil at amino acids 1074-1103. Further along the protein are multiple AAA domains (ATPases Associated with various cellular Activities), including 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 is found between amino acids 2881-3169, which also contains two Coiled coil domains (amino acids 2897-2982 and 3109-3200). Another Coiled coil is located at amino acids 3408-3442.
Key variants
Genetic variations, or variants, within the DYNC2H1 gene can alter the protein's structure and function. Pathogenic variants can impair the protein's ability to facilitate intraflagellar transport within cilia, leading to a range of developmental abnormalities. These variants are typically inherited in an autosomal recessive manner, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to develop a condition.
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.4484_4488del | p.Asn1495fs | Pathogenic/Likely pathogenic | ★★☆☆ | DYNC2H1-related disorder |
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 |
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
Mutations in the DYNC2H1 gene are known to cause several skeletal ciliopathies, primarily Jeune asphyxiating thoracic dystrophy. They are also implicated in various Short-rib polydactyly syndromes, such as type II (Majewski syndrome) and type III (Verma-Naumoff syndrome or Saldino-Noonan syndrome). These conditions are characterised by severe bone growth abnormalities, often affecting the chest, ribs, and limbs.
- 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 included in several UK NHS national genomic testing panels, indicating its recognised clinical significance within the UK healthcare system. It is present on panels for 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 relevance for diagnosing a range of inherited conditions affecting skeletal and ciliary development.
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 making a protein that is part of the dynein-2 complex. This complex is crucial for intraflagellar transport (IFT), which moves materials within cilia, vital for cell signalling and development.
What conditions are associated with DYNC2H1 gene mutations?
Mutations in the DYNC2H1 gene are associated with several skeletal ciliopathies, including Jeune asphyxiating thoracic dystrophy and various Short-rib polydactyly syndromes.
How is DYNC2H1 gene-related conditions inherited?
Conditions linked to DYNC2H1 gene mutations are typically inherited in an autosomal recessive manner. This means an individual must inherit two affected copies of the gene, one from each parent, to develop the condition.
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