DST Gene

The DST gene (DST stands for "dystonin") is a protein-coding gene located on chromosome 6p12.1. DST encodes a member of the plakin protein family which belong to the adhesion junction proteins. Several alternatively spliced transcript variants have been found for this gene, encoding different isoforms, some of which have not yet been elucidated in their structure. Some isoforms have been reported to be expressed in neural and muscle tissue and to anchor neural intermediate filaments to the actin cytoskeleton, whereas some isoforms are expressed in epithelial tissue and anchor keratin-containing intermediate filaments to hemidesmosomes. In animal experiments, skin blistering and neurodegeneration could be induced when the gene was defective.

The encoded protein, BP230 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. The protein is involved in the organization and stability of the microtubule network of sensory neurons to allow axonal transport. Mediates the docking of the dynein/dynactin motor complex to vesicle cargoes for retrograde axonal transport through its interaction with TMEM108 and DCTN1.

Isoform 3 of the protein 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; mediates regulation of RAC1 activity through integrin ITGB4.

Isoform 6 is required for actin filament bundling around the nucleus.

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

Autoantibodies against Bp230 lead to vesicular autoimmune diseases.

Diseases associated with dystonin include:

• Epidermolysis Bullosa Simplex 3, localized or generalized intermediate, with Bp230 deficiency /OMIM: 615425) a mild, autosomal recessive inherited genodermatosis characterized by traumatically induced blistering occurring mainly on the mechanically exposed areas of the feet and ankles. 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

and

• Neuroblastoma: For pediatric neuroblastoma, MYCN amplifications and age itself are two crucial prognostic factors. It has been shown that the age-related gene DST is an independent prognostic factor in non-amplified MYCN neuroblastoma. Younger patients with non-MYCN-amplified neuroblastoma and higher DST expression had the best overall clinical survival (Wang H et al. 2021).

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

Antibody formations against the encoded protein (BP230) lead to autoimmune diseases:

• Bullous pemphigoid (BP180; BP230).
• Lichen planus pemphigoides (BP180; BP230, 200 KDa protein)
• Pemphigoid gestationis (BP180; BP230)

1. Cappuccio G et al (2017) Expanding the phenotype of DST-related disorder: A case report suggesting a genotype/phenotype correlation. Am J Med Genet A 173:2743-2746.
2. Ganani D et al. (2021) Epidermolysis bullosa simplex due to bi-allelic DST mutations: case series and review of the literature. Pediatr Dermatol. 38:436-441.
3. 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 Dermatol 130:1551-1557.

4. 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.

5. Liu L et al (2021) Autosomal recessive epidermolysis bullosa simplex due to loss of BPAG1-e expression. (Letter) J Invest Derm 132: 742-744.

6. Stanley JR et al (1981) Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell 24:897-903.
7. Wang H et al (2021) Age related gene DST represents an independent prognostic factor for MYCN non-amplified neuroblastoma. BMC Pediatr 21:272.