DCTN1 and Amyotrophic Lateral Sclerosis

Clinical Validity

The association between heterozygous DCTN1 variants and autosomal dominant amyotrophic lateral sclerosis (ALS) is supported by multiple independent reports of rare coding mutations in ALS patients and familial segregation in pedigrees. Overall, the gene–disease association is classified as Moderate based on ClinGen criteria. Specifically, at least 9 unrelated probands with heterozygous DCTN1 variants have been described in ALS cohorts and case series (excluding related individuals) and 4 additional affected relatives show variant segregation in independent families ([PMID:16240349]; [PMID:18852346]). Functional concordance with disrupted dynactin complex activity further strengthens the evidence.

Genetic Evidence

ALS patients harbor diverse heterozygous DCTN1 missense variants, predominantly acting in an autosomal dominant fashion. A family with the recurrent c.3302G>A (p.Arg1101Lys) variant exhibited two members with motor neuron disease and two with frontotemporal dementia, segregating over two generations ([PMID:16240349]). Sporadic ALS screens identified novel DCTN1 variants including c.2989C>T (p.Arg997Trp) in one of 35 cases ([PMID:18852346]), c.175G>C (p.Gly59Arg) with cosegregation in a small pedigree ([PMID:25109764]), and rare variants c.1867C>T (p.Arg623Trp) and c.2798C>T (p.Ala933Val) in 2 of 510 Chinese sporadic ALS patients ([PMID:28792508]). These 9 unrelated variant carriers, combined with segregation data, yield a Moderate level of genetic evidence under ClinGen.

Functional Evidence

Experimental studies demonstrate that pathogenic DCTN1 variants disrupt dynactin–dynein function and promote protein aggregation. The G59S mutant exhibits impaired microtubule binding and forms cytotoxic aggregates cleared less efficiently via the proteasome–autophagy axis; overexpression of TFEB enhances autophagic removal of aggregates ([PMID:31654383]). DCTN1 p.Gly71Ala impairs interaction with TDP-43, triggering cytoplasmic mislocalization and aggregation of TDP-43 in cellular assays ([PMID:33924373]). These concordant experiments support a Moderate level of functional evidence, consistent with a dominant‐negative mechanism.

Conflicting Evidence

Population‐based sequencing in 286 neurodegeneration cases, including ALS, failed to identify DCTN1 variants segregating with disease or enriched risk alleles, suggesting pathogenic mutations are rare and not a common risk factor ([PMID:19506225]). Similarly, large sporadic ALS panels show a variant frequency of <0.5%, indicating DCTN1 contributes to a minority of ALS cases.

Conclusion

Heterozygous DCTN1 variants are a moderate but clinically actionable cause of autosomal dominant ALS. Rare missense mutations impair microtubule binding and protein homeostasis, consistent with neurodegeneration. Screening for DCTN1 variants should be considered in familial and sporadic ALS when common ALS genes are negative. Key Take-home: DCTN1 should be included in ALS gene panels, as rare dominant variants confer ALS risk and may inform diagnosis and genetic counseling.

References

• Annals of neurology • 2005 • Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD PMID:16240349
• Archives of neurology • 2008 • Development of a high-throughput microarray-based resequencing system for neurological disorders and its application to molecular genetics of amyotrophic lateral sclerosis PMID:18852346
• Neurobiology of aging • 2014 • Identify mutation in amyotrophic lateral sclerosis cases using HaloPlex target enrichment system PMID:25109764
• Neurotoxicity research • 2020 • Autophagy and Ubiquitin-Proteasome System Coordinate to Regulate the Protein Quality Control of Neurodegenerative Disease-Associated DCTN1 PMID:31654383
• International journal of molecular sciences • 2021 • DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation PMID:33924373
• Neurology • 2009 • Characterization of DCTN1 genetic variability in neurodegeneration PMID:19506225

Evidence Based Scoring (AI generated)