DCTN1 – Distal Hereditary Motor Neuropathy Type 7B

Distal hereditary motor neuropathy type 7B (dHMN7B) is an autosomal dominant distal motor neuropathy characterized by progressive distal muscle weakness and atrophy. DCTN1 encodes p150Glued, the largest subunit of the dynactin complex essential for cytoplasmic dynein–mediated retrograde axonal transport.

Heterozygous DCTN1 variants have been identified in multiple dHMN7B families. The c.279G>C (p.Gln93His) mutation cosegregated with dHMN7B and Perry syndrome phenotypes in a Chinese pedigree (PMID:33443672). The recurrent c.175G>C (p.Gly59Arg) variant was observed in siblings with dHMN7B and amyotrophic lateral sclerosis, demonstrating intrafamilial phenotypic heterogeneity (PMID:34615428). A frameshift allele c.626dupC (p.Leu210AlafsTer?) was reported in a patient with early-onset dHMN and congenital foot deformity, confirmed by functional studies (PMID:32023010). These three unrelated pedigrees encompass three probands with segregation of DCTN1 CAP-Gly domain mutations.

All dHMN7B-associated mutations localize to the N-terminal CAP-Gly domain or adjacent regions of DCTN1, disrupting microtubule binding. The missense changes p.Gln93His and p.Gly59Arg alter conserved residues within the CAP-Gly motif, while p.Leu210AlafsTer truncates the domain and abolishes α-tubulin interaction.

Functional assays confirm pathogenicity: in silico modeling of p.Gln93His predicts loss of a hydrogen bond critical for CAP-Gly stability (PMID:33443672). The p.Leu210AlafsTer mutant exhibits nuclear mislocalization and loss of microtubule colocalization in cell models (PMID:32023010). These data support a dominant-negative or haploinsufficiency mechanism impairing axonal transport.

No studies have refuted the specific association of DCTN1 variants with dHMN7B. Population screens in ALS, FTD, and parkinsonism cohorts did not identify CAP-Gly domain mutations, underscoring their rarity and disease specificity (PMID:19506225).

In summary, autosomal dominant dHMN7B is caused by heterozygous DCTN1 CAP-Gly domain mutations that impair dynactin function and retrograde transport. Additional large-scale segregation and rescue studies would further solidify this association. Key take-home: DCTN1 genetic testing is essential for definitive diagnosis and genetic counseling in dHMN7B.

References

• Neurological sciences • 2021 • A novel Q93H missense mutation in DCTN1 caused distal hereditary motor neuropathy type 7B and Perry syndrome from a Chinese family. PMID:33443672
• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2022 • An identical DCTN1 mutation in two Chinese siblings manifest as dHMN and ALS respectively: a case report. PMID:34615428
• Annals of clinical and translational neurology • 2020 • New phenotype of DCTN1-related spectrum: early-onset dHMN plus congenital foot deformity. PMID:32023010
• Neurology • 2009 • Characterization of DCTN1 genetic variability in neurodegeneration. PMID:19506225

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