DST gene

DST (dystonin) is a protein-coding gene located on chromosome 6p12.1. The gene encodes a member of the plakin protein family of adhesion junction proteins. Several alternatively spliced transcript variants have been found for this gene, encoding different isoforms whose full-length nature has not yet been defined.

Some isoforms are expressed in neural and muscle tissue and anchor neural intermediate filaments to the actin cytoskeleton, whereas other isoforms are expressed in epithelial tissue and anchor keratin-containing intermediate filaments to hemidesmosomes. In animal experiments, mice, with mutations in this gene, show skin blistering and neurodegeneration.

The encoded dystonin protein acts as an integrator of intermediate filament, actin and microtubule cytoskeleton networks. It is required for anchoring intermediate filaments to the actin cytoskeleton in nerve and muscle cells or keratin-containing intermediate filaments to hemidesmosomes in epithelial cells. The proteins can self-aggregate to form filaments or a two-dimensional network. Furthermore, dystonin regulates the organization and stability of the microtubule network of sensory neurons to enable axonal transport. Mediates docking of the dynein/dynactin motor complex to vesicle cargoes for retrograde axonal transport through its interaction with TMEM108 and DCTN1.

Isoform 3 plays a structural role in the assembly of hemidesmosomes of epithelial cells; anchors keratin-containing intermediate filaments to the inner plaque of hemidesmosomes. Required for regulation of keratinocyte polarity and motility.

Isoform 6 is required for the bundling of actin filaments around the nucleus.

Isoform 7 regulates the organization and stability of the microtubule network of sensory neurons to allow axonal transport.

Diseases associated with dystonin include:

• Epidermolysis bullosa simplex, autosomal recessive with Bp230 deficiency (EBS3)/OMIM: 615425) a mild, autosomal recessive inherited genodermatosis characterized by traumatically induced blistering occurring mainly on the mechanically exposed areas of the feet and ankle parts. Ultrastructural analysis of skin biopsies shows abnormal formation of hemidesmosomes with poorly formed internal plaques (Liu et al. 2012).
• the neuropathy, hereditary sensory and autonomic, type Vi
• the axonal Charcot-Marie-Tooth disease

High expression of DST is associated with favorable prognosis in breast carcinoma. Apparently, DST is able to influence the development and progression of BRCA by altering the immune microenvironment (Qiu X et al. 2022).

1. Ganani D et al. (2021) Epidermolysis bullosa simplex due to bi-allelic DST mutations: case series and review of the literature. Pediat. Derm 38: 436-441.
2. Groves RW et al. (2010) A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. J Invest Derm 130: 1551-1557.
3. Qiu X et al (2022) Identification of m6A-Associated Gene DST as a Prognostic and Immune-Associated Biomarker in Breast Cancer Patients. Int J Gen Med15:523-534.
4. Liu L et al (2021) Autosomal recessive epidermolysis bullosa simplex due to loss of BPAG1-e expression. (Letter) J Invest Derm 132: 742-744.