DST and Associated Diseases
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Overview of DST
The human DST gene is located on chromosome 6p12 and is 500 kb long, while the mouse DST gene is located on chromosome 1 and is about 400 kb long. In rodents, DST has four tissue-specific promoters expressing dystonin in the epidermis, central and peripheral nervous systems, and muscle. The dystonin neuronal and muscle transcripts encode three predominant isoforms. Isoform 1 has a short N-terminal unique region, isoform 2 has an N-terminal transmembrane domain, and isoform 3 has a putative N-terminal myristoylation motif. Since the dystonin proteins belong to the spectraplakin family of proteins, they function as cytoskeletal linkers responsible for maintaining structural integrity and mediating processes such as intracellular trafficking. Homozygous mutations in the human DST gene were found to be associated with a severe phenotype that shared many features with a subset of genetic disorders known as hereditary sensory and autonomic neuropathy.
Fig.1 Schematic diagram of the dystonin gene. (Ferrier, 2013)
Dystonin Deficiency in Murine and Cell Culture Models
- Dystonia Musculorum (dt) Mice
The dt mouse is an autosomal-recessive mutant of the Dst gene. Deficiency in dystonin expression within the nervous system leads to the dt phenotype. The dt phenotype is characterized as a loss of limb coordination beginning at 7-10 days postnatal development.
- Affected Cell Types of dt Mice
Dt syndrome affects other cell types in addition to sensory neuron degeneration. For example, axonal enlargement is indistinguishable from sensory axons and is present in both ventral roots and certain ventral processes during the phenotypic phase.
- Hallmark Pathologies of dt Sensory Neurons
Since the mouse model of dt has similar pathological features to human neurodegenerative diseases, a better understanding of the pathogenesis of dt will contribute to a deeper understanding of the etiology of human neurological diseases.
- Mechanisms of dt Sensory Neuron Degeneration
The disorganized cytoskeletal networks, particularly microtubules (MTs), in dt sensory neurons, led to the presumption that axonal transport was likely defective and eventually caused dt neurodegeneration. Transport defects are mediated by perturbation of the dystonin-a/dynein complex and underlie dt sensory neuron death.
DST in Disease
In mice, the neurodegenerative disorder dt has been demonstrated to involve axonal neurofilament aggregation and axonal microtubule disorganization in sensory neurons. The dt disorder is caused by mutations in the dystonin (DST; Bpag1) gene, which codes for cytoskeletal cross-linking proteins. DST dysfunction mutations can lead to hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). DST-related diseases are believed to be more complex than previously thought, because one patient presents with both neurological and cutaneous manifestations, while others show only one or the other. Recent studies have shown that missing a copy of the DST gene, or the presence in humans of truncated forms of the mutant protein can lead to partial disruption of sensory and motor circuits. Mutations in the mouse DST gene have previously been shown to cause sensory neuron degeneration and skin fragility.
Fig.2 Neuronal defects in dt mice include early abnormal F-actin punctae and a widespread loss of Nissl staining. (Young, 2008)
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References
- Ferrier, A.; et al. Cellular and molecular biology of neuronal dystonin. Int Rev Cell Mol Biol. 2013, 300: 85-120.
- Young, K.G.; Kothary, R. Dystonin/Bpag1 is a necessary endoplasmic reticulum/nuclear envelope protein in sensory neurons. Exp Cell Res. 2008, 314: 2750-61.
