DCTN1

dynactin subunit 1, the group of Dynactin subunits

Basic information

Region (hg38): 2:74361153-74392087

Links

ENSG00000204843 ∙ NCBI:1639 ∙ OMIM:601143 ∙ HGNC:2711 ∙ Uniprot:Q14203 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• distal hereditary motor neuropathy type 7 (Supportive), mode of inheritance: AD
• Perry syndrome (Supportive), mode of inheritance: AD
• Perry syndrome (Strong), mode of inheritance: AD
• Perry syndrome (Moderate), mode of inheritance: AD
• neuronopathy, distal hereditary motor, type 7B (Moderate), mode of inheritance: AD
• amyotrophic lateral sclerosis type 1 (Strong), mode of inheritance: AD
• neuronopathy, distal hereditary motor, type 7B (Strong), mode of inheritance: AD
• amyotrophic lateral sclerosis (Moderate), mode of inheritance: AD
• neuronopathy, distal hereditary motor, type 7B (Strong), mode of inheritance: AD
• Perry syndrome (Strong), mode of inheritance: AD
• amyotrophic lateral sclerosis type 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Perry syndrome	AD	Neurologic; Pulmonary	In Perry syndrome, individuals may manifest with severe and potentially lethal hypoventilation, and interventions including aggressive pulmonary as well as medical management (eg, carbidopa/levodopa) may be beneficial	Neurologic; Pulmonary	1122173; 43704; 3352925; 2247238; 11940687; 12627231; 15326253; 19136952; 20437543; 20702129; 20945553; 24343258

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DCTN1 gene.

• Amyotrophic lateral sclerosis type 1;Neuronopathy, distal hereditary motor, type 7B;Perry syndrome (405 variants)
• Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B (216 variants)
• not provided (189 variants)
• Inborn genetic diseases (178 variants)
• Perry syndrome;Amyotrophic lateral sclerosis type 1;Neuronopathy, distal hereditary motor, type 7B (116 variants)
• Perry syndrome (96 variants)
• Neuronopathy, distal hereditary motor, type 7B;Amyotrophic lateral sclerosis type 1;Perry syndrome (96 variants)
• Neuronopathy, distal hereditary motor, type 7B (94 variants)
• not specified (27 variants)
• Perry syndrome;Neuronopathy, distal hereditary motor, type 7B;Amyotrophic lateral sclerosis type 1 (27 variants)
• Neuronopathy, distal hereditary motor, type 7B;Perry syndrome;Amyotrophic lateral sclerosis type 1 (27 variants)
• DCTN1-related condition (15 variants)
• Amyotrophic lateral sclerosis (7 variants)
• Amyotrophic lateral sclerosis type 1 (5 variants)
• Amyotrophic lateral sclerosis, susceptibility to (3 variants)
• Hereditary motor neuron disease (3 variants)
• See cases (2 variants)
• Charcot-Marie-Tooth disease (2 variants)
• Neuronopathy, distal hereditary motor (2 variants)
• DCTN1-Related Disorder (2 variants)
• DCTN1-Related Disorders (1 variants)
• Amyotrophic lateral sclerosis type 1;Perry syndrome (1 variants)
• Generalized dystonia;Dystonic disorder (1 variants)
• Peripheral neuropathy (1 variants)
• Parkinsonism (1 variants)
• Charcot-Marie-Tooth disease type 2 (1 variants)
• Frontotemporal dementia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DCTN1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			8	196	6	210
missense	4	4	447	20	3	478
nonsense			8			8
start loss			1			1
frameshift	1		5			6
inframe indel			6			6
splice donor/acceptor (+/-2bp)	1		11			12
splice region			36	41	4	81
non coding			17	138	40	195
Total	6	4	503	354	49

Variants in DCTN1

This is a list of pathogenic ClinVar variants found in the DCTN1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-74361248-A-C		Neuronopathy, distal hereditary motor, type 7B • Perry syndrome	Uncertain significance (Jan 12, 2018)
2-74361332-G-A		Perry syndrome • Neuronopathy, distal hereditary motor, type 7B	Benign (Jan 13, 2018)
2-74361377-T-G		Neuronopathy, distal hereditary motor, type 7B • Perry syndrome	Benign (Jan 13, 2018)
2-74361388-G-A		Neuronopathy, distal hereditary motor, type 7B • Perry syndrome	Uncertain significance (Jan 12, 2018)
2-74361442-G-A		Perry syndrome • Neuronopathy, distal hereditary motor, type 7B	Benign (Jan 12, 2018)
2-74361450-C-T		Neuronopathy, distal hereditary motor, type 7B • Perry syndrome	Likely benign (Jan 13, 2018)
2-74361478-G-A		Perry syndrome • Neuronopathy, distal hereditary motor, type 7B	Benign (Jan 13, 2018)
2-74361502-G-A		Amyotrophic lateral sclerosis type 1;Neuronopathy, distal hereditary motor, type 7B;Perry syndrome	Likely benign (Sep 03, 2022)
2-74361506-A-G		Amyotrophic lateral sclerosis type 1;Neuronopathy, distal hereditary motor, type 7B;Perry syndrome	Uncertain significance (Apr 21, 2022)
2-74361508-G-A		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B	Likely benign (Feb 22, 2023)
2-74361512-C-T		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B • Inborn genetic diseases	Uncertain significance (Jul 19, 2022)
2-74361513-G-A		Neuronopathy, distal hereditary motor, type 7B;Amyotrophic lateral sclerosis type 1;Perry syndrome	Likely pathogenic (Oct 14, 2023)
2-74361516-T-G		Amyotrophic lateral sclerosis type 1;Neuronopathy, distal hereditary motor, type 7B;Perry syndrome	Uncertain significance (May 02, 2022)
2-74361525-G-C		Neuronopathy, distal hereditary motor, type 7B;Amyotrophic lateral sclerosis type 1;Perry syndrome	Uncertain significance (Jan 30, 2020)
2-74361526-G-T		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B	Uncertain significance (Sep 16, 2021)
2-74361533-T-C		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B	Uncertain significance (Jan 01, 2023)
2-74361537-C-G		Neuronopathy, distal hereditary motor, type 7B • Perry syndrome • Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B • Inborn genetic diseases	Conflicting classifications of pathogenicity (May 25, 2023)
2-74361537-C-T		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B	Benign/Likely benign (Jan 27, 2024)
2-74361539-T-C		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B	Uncertain significance (Jan 28, 2023)
2-74361540-G-T		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B	Uncertain significance (Mar 29, 2023)
2-74361549-C-T		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B	Uncertain significance (Nov 22, 2022)
2-74361553-C-A		Neuronopathy, distal hereditary motor, type 7B;Perry syndrome;Amyotrophic lateral sclerosis type 1 • DCTN1-related disorder	Likely benign (Dec 06, 2022)
2-74361554-C-T		Perry syndrome • Neuronopathy, distal hereditary motor, type 7B • Perry syndrome;Neuronopathy, distal hereditary motor, type 7B;Amyotrophic lateral sclerosis type 1 • DCTN1-related disorder	Benign/Likely benign (Feb 28, 2024)
2-74361555-G-A		Amyotrophic lateral sclerosis type 1;Perry syndrome;Neuronopathy, distal hereditary motor, type 7B	Uncertain significance (Jun 30, 2023)
2-74361556-G-A		Amyotrophic lateral sclerosis type 1;Neuronopathy, distal hereditary motor, type 7B;Perry syndrome	Likely benign (Nov 23, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DCTN1	protein_coding	protein_coding	ENST00000361874	32	30934

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0843	0.916	125707	0	41	125748	0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.892	642	709	0.906	0.0000462	8238
Missense in Polyphen		187	268.55	0.69632		3336
Synonymous	-0.793	301	284	1.06	0.0000169	2600
Loss of Function	5.88	17	70.1	0.242	0.00000409	824

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000394	0.000394
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00	0.00
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000180	0.000176
Middle Eastern	0.00	0.00
South Asian	0.000136	0.000131
Other	0.000335	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a key role in dynein-mediated retrograde transport of vesicles and organelles along microtubules by recruiting and tethering dynein to microtubules. Binds to both dynein and microtubules providing a link between specific cargos, microtubules and dynein. Essential for targeting dynein to microtubule plus ends, recruiting dynein to membranous cargos and enhancing dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Can also act as a brake to slow the dynein motor during motility along the microtubule (PubMed:25185702). Can regulate microtubule stability by promoting microtubule formation, nucleation and polymerization and by inhibiting microtubule catastrophe in neurons. Inhibits microtubule catastrophe by binding both to microtubules and to tubulin, leading to enhanced microtubule stability along the axon (PubMed:23874158). Plays a role in metaphase spindle orientation (PubMed:22327364). Plays a role in centriole cohesion and subdistal appendage organization and function. Its recruitement to the centriole in a KIF3A-dependent manner is essential for the maintenance of centriole cohesion and the formation of subdistal appendage. Also required for microtubule anchoring at the mother centriole (PubMed:23386061). Plays a role in primary cilia formation (PubMed:25774020). {ECO:0000269|PubMed:22327364, ECO:0000269|PubMed:23386061, ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:25185702, ECO:0000269|PubMed:25774020}.
• Disease: DISEASE: Neuronopathy, distal hereditary motor, 7B (HMN7B) [MIM:607641]: A neuromuscular disorder. Distal hereditary motor neuronopathies constitute a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. {ECO:0000269|PubMed:12627231, ECO:0000269|PubMed:16505168, ECO:0000269|PubMed:19136952, ECO:0000269|PubMed:19279216, ECO:0000269|PubMed:22777741}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Amyotrophic lateral sclerosis (ALS) [MIM:105400]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:15326253, ECO:0000269|PubMed:16240349}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Perry syndrome (PERRYS) [MIM:168605]: A neuropsychiatric disorder characterized by mental depression not responsive to antidepressant drugs or electroconvulsive therapy, sleep disturbances, exhaustion and marked weight loss. Parkinsonism develops later and respiratory failure occurred terminally. {ECO:0000269|PubMed:19136952, ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:24676999, ECO:0000269|PubMed:24881494, ECO:0000269|PubMed:25185702, ECO:0000269|PubMed:26972003}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Vasopressin-regulated water reabsorption - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);XBP1(S) activates chaperone genes;Vesicle-mediated transport;lissencephaly gene (lis1) in neuronal migration and development;Membrane Trafficking;Post-translational protein modification;Metabolism of proteins;Regulation of PLK1 Activity at G2/M Transition;Transport to the Golgi and subsequent modification;Asparagine N-linked glycosylation;Recruitment of mitotic centrosome proteins and complexes;Loss of Nlp from mitotic centrosomes;Loss of proteins required for interphase microtubule organization from the centrosome;Centrosome maturation;AURKA Activation by TPX2;G2/M Transition;Mitotic G2-G2/M phases;COPI-independent Golgi-to-ER retrograde traffic;Golgi-to-ER retrograde transport;Recruitment of NuMA to mitotic centrosomes;Mitotic Prometaphase;COPI-mediated anterograde transport;M Phase;Cell Cycle;ER to Golgi Anterograde Transport;Cell Cycle, Mitotic;Anchoring of the basal body to the plasma membrane;N-cadherin signaling events;Intra-Golgi and retrograde Golgi-to-ER traffic;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.505

Intolerance Scores

• loftool: 0.0211
• rvis_EVS: -0.88
• rvis_percentile_EVS: 10.58

Haploinsufficiency Scores

• pHI: 0.517
• hipred: Y
• hipred_score: 0.756
• ghis: 0.611

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.631

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Dctn1
• Phenotype: skeleton phenotype; immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: dctn1a
• Affected structure: retinal bipolar neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: G2/M transition of mitotic cell cycle;establishment of mitotic spindle orientation;mitotic cell cycle;endoplasmic reticulum to Golgi vesicle-mediated transport;nervous system development;neuromuscular junction development;regulation of G2/M transition of mitotic cell cycle;centriole-centriole cohesion;antigen processing and presentation of exogenous peptide antigen via MHC class II;ventral spinal cord development;positive regulation of microtubule polymerization;microtubule anchoring at centrosome;IRE1-mediated unfolded protein response;retrograde transport, endosome to Golgi;neuromuscular process;nuclear envelope disassembly;cell division;regulation of mitotic spindle organization;motor behavior;neuron cellular homeostasis;positive regulation of microtubule nucleation;ciliary basal body-plasma membrane docking;axonal transport;maintenance of synapse structure;positive regulation of neuromuscular junction development;non-motile cilium assembly;neuron projection maintenance
• Cellular component: kinetochore;spindle pole;nuclear envelope;cytoplasm;centrosome;centriole;spindle;cytosol;dynactin complex;microtubule;microtubule associated complex;cell cortex;membrane;dynein complex;axon;retromer complex;microtubule plus-end;neuron projection;neuronal cell body;intermediate filament cytoskeleton;cell cortex region;centriolar subdistal appendage
• Molecular function: motor activity;protein binding;microtubule binding;tubulin binding;protein kinase binding;tau protein binding;dynein complex binding