DCTN1 – Perry syndrome

DCTN1 encodes the p150Glued subunit of dynactin, essential for dynein-mediated retrograde transport. Perry syndrome is a rare autosomal dominant neurodegenerative disorder characterized by midlife-onset parkinsonism, central hypoventilation, weight loss, depression, and TDP-43 pathology. Genetic linkage and sequencing studies have firmly established DCTN1 mutations as causative.

Initial genome-wide linkage in eight families identified five segregating missense variants clustering in the CAP-Gly domain, including c.211G>A (p.Gly71Arg), demonstrating impaired microtubule binding and intracytoplasmic inclusions (PMID:19136952). Subsequent reports expanded the spectrum to 20 families with 87 affected individuals worldwide, confirming autosomal dominant inheritance and recurrent Gly71 and Tyr78 substitutions (PMID:32434902).

The variant spectrum comprises predominantly missense changes in exon 2: Gly71Arg, Gly71Glu, Thr72Pro, Gln74Pro, Phe52Leu, Tyr78Cys, and Tyr78His. The recurrent c.211G>A (p.Gly71Arg) illustrates a mutational hotspot within the CAP-Gly motif essential for microtubule engagement (PMID:19136952).

Functional studies reveal that Perry-linked DCTN1 mutants impair microtubule binding in vitro and form cytoplasmic aggregates in patient-derived iPSC neurons, recapitulating dynactin aggregation and TDP-43 pathology (PMID:27346608). Transgenic DCTN1G71A mice manifest apathy-like behavior and motor coordination deficits, paralleling human phenotypes (PMID:29273399).

Bioinformatic modeling of Tyr78His and other CAP-Gly variants predicts destabilization of the p150Glued fold and altered interaction with MAPRE1, supporting a dominant-negative mechanism (PMID:32712562).

No significant conflicting evidence has emerged; DCTN1 variants outside exon 2 have not been linked to Perry syndrome phenotypes. The combined genetic segregation across 20 families, functional concordance in cellular and animal models, and absence in population controls establish a definitive association.

Key Take-Home: Heterozygous missense mutations in DCTN1 should be sought in patients with familial parkinsonism, hypoventilation, weight loss, and depression, as early diagnosis enables ventilatory support and genetic counseling.

References

• Nature Genetics • 2009 • DCTN1 mutations in Perry syndrome. PMID:19136952
• Practical neurology • 2020 • DCTN1-related Parkinson-plus disorder (Perry syndrome). PMID:32434902
• Parkinsonism & related disorders • 2016 • Cytoplasmic aggregates of dynactin in iPSC-derived tyrosine hydroxylase-positive neurons from a patient with Perry syndrome. PMID:27346608
• Neuroscience letters • 2018 • Behavioral defects in a DCTN1G71A transgenic mouse model of Perry syndrome. PMID:29273399
• Parkinsonism & related disorders • 2020 • Novel destabilizing Dynactin variant (DCTN1 p.Tyr78His) in patient with Perry syndrome. PMID:32712562

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