DCTN1

Chr 2ADAR

dynactin subunit 1

Also known as: DAP-150, DP-150, HMND14, P135

NCBI Gene: 1639 ENSG00000204843 UniProt: Q14203

This gene encodes the largest subunit of dynactin, a macromolecular complex consisting of 10 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein. Dynactin is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit interacts with dynein intermediate chain by its domains directly binding to dynein and binds to microtubules via a highly conserved glycine-rich cytoskeleton-associated protein (CAP-Gly) domain in its N-terminus. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause distal hereditary motor neuronopathy type VIIB (HMN7B) which is also known as distal spinal and bulbar muscular atrophy (dSBMA). [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

{Amyotrophic lateral sclerosis, susceptibility to}MIM #105400

ADAR

Neuronopathy, distal hereditary motor, autosomal dominant 14MIM #607641

Perry syndromeMIM #168605

Active trials

Pathogenic / LP

384

ClinVar variants

Pubs (1 yr)

0.9

Missense Z

0.36

LOEUF

Clinical Summary— DCTN1

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Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

7 Pathogenic / Likely Pathogenic· 230 VUS of 384 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — DCTN1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.36LOEUF

pLI 0.084

Z-score 5.88

OE 0.24 (0.17–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

0.89Z-score

OE missense 0.91 (0.85–0.97)

642 obs / 708.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.24 (0.17–0.36)

0≤0.351.4

Missense OE0.91 (0.85–0.97)

0≤0.61.4

Synonymous OE1.06

0≤1.21.6

LoF obs/exp: 17 / 70.1Missense obs/exp: 642 / 708.9Syn Z: -0.79

Badonyi & Marsh 2024 ↗

0.6162th %ile

GOF

0.5562th %ile

LOF

0.4529th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DN1 literature citation

Literature Evidence

DNA Novel Cosegregating DCTN1 Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology. This variant is analogous to the dominant-negative GLUED Gl1 mutation in Drosophila, which is responsible for a neurodegenerative phenotype.PMID:32325768

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.