DST

Chr 6AR

dystonin

Also known as: BP240, BPA, BPAG1, CATX-15, CATX15, CMYO29, D6S1101, DMH

NCBI Gene: 667 ENSG00000151914 UniProt: Q03001 OMIM: 113810

The DST protein is a cytoskeletal linker that integrates intermediate filaments, actin, and microtubule networks, anchoring intermediate filaments to the actin cytoskeleton in neural and muscle cells and keratin filaments to hemidesmosomes in epithelial cells. Autosomal recessive mutations cause congenital myopathy with contractures, lethal congenital contracture syndrome, hereditary sensory and autonomic neuropathy type VI, and epidermolysis bullosa simplex with skin blistering. This gene is highly constrained against loss-of-function variants, reflecting its critical role in maintaining cytoskeletal integrity across multiple tissue types including skin, muscle, and peripheral nerves.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the plakin protein family of adhesion junction plaque proteins. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the full-length nature of some variants has not been defined. It has been reported that some isoforms are expressed in neural and muscle tissue, anchoring neural intermediate filaments to the actin cytoskeleton, and some isoforms are expressed in epithelial tissue, anchoring keratin-containing intermediate filaments to hemidesmosomes. Consistent with the expression, mice defective for this gene show skin blistering and neurodegeneration. [provided by RefSeq, Mar 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Congenital myopathy 29 with contracturesMIM #621510

Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiencyMIM #615425

Lethal congenital contracture syndrome 12MIM #621511

Neuropathy, hereditary sensory and autonomic, type VIMIM #614653

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hereditary sensory and autonomic neuropathy type 6 · AR · ClinGen 2021

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

668

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — DST

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 13.32

OE 0.14 (0.10–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.22Z-score

OE missense 0.88 (0.84–0.91)

2223 obs / 2537.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.14 (0.10–0.18)

0≤0.351.4

Missense OE?0.88 (0.84–0.91)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 38 / 277.4Missense obs/exp: 2223 / 2537.8Syn Z: 0.43

Background carrier burden — how many people carry a rare variant somewhere in DST?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 6

11,435 rare PASS variants

Rare truncating (LoF)

1 in 97

979 rare PASS variants

Rare synonymous (reference)

1 in 11

4,287 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DST. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 8	1 in 120
South Asian	~43k	1 in 5	1 in 120
Remaining (unassigned)	~30k	1 in 5	1 in 160
European (Finnish)	~27k	1 in 17	1 in 470
Admixed American	~22k	1 in 6	1 in 160
African / African American	~21k	1 in 5	1 in 96
East Asian	~20k	1 in 6	1 in 120
Ashkenazi Jewish	~13k	1 in 22	1 in 320
Middle Eastern	~2,884	1 in 6	1 in 140

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 58 of 104 coding exons well covered in gnomAD exomes; exons 6, 7, 14 poorly covered; exons 1, 2, 3, 5, 8 and 38 more marginal. Genomes: all 104.? see exons ↓