Objective: To identify novel mutations in DCTN1 associated with autosomal dominant Perry syndrome and investigate their potential pathogenic mechanisms.

Background: Perry syndrome is a neurodegenerative disorder characterized by early-onset parkinsonism, rapid progression, depression, weight loss, and hypoventilation, leading to respiratory failure. Mutations in the CAP-GLY domain of DCTN1 have been implicated, but we report two novel pathogenic loci, including one outside this domain, suggesting alternative disease mechanisms.

Method: Whole-genome and whole-exome sequencing were conducted in patients with early-onset Parkinson’s disease (PD) or atypical parkinsonian disorders (APD) after excluding known PD-associated mutations. Two novel DCTN1 heterozygous mutations were identified. Clinical, neuropsychological, and neuroimaging assessments were performed, alongside cellular transfection and immunocytochemistry analyses.

Results: A novel heterozygous DCTN1 mutation, c.94C>T (p.Arg32Cys), was identified in a patient clinically diagnosed with progressive supranuclear palsy (PSP). This patient exhibited a spectrum of non-motor symptoms, including urinary urgency, REM sleep behavior disorder (RBD), hyposmia, and cognitive decline, along with personality changes, social withdrawal, and anxiety. The patient also presented with restrictive pulmonary dysfunction. The p.Arg32Cys mutation resides outside the CAP-Gly domain, expanding the pathogenic spectrum of DCTN1 mutations. Another novel heterozygous DCTN1 mutation, c.199G>A (p.Gly67Ser), was found in a patient with early-onset PD presenting with bradykinesia and rigidity at age 47. Disease progression remains unknown due to loss to follow-up. Both mutations were rare or absent in control cohorts, predicted to be highly pathogenic by in silico analysis, and demonstrated interspecies conservation. Functional studies revealed altered subcellular localization of p150glued protein and abnormal cytoplasmic distribution of TDP-43.

Conclusion: Our findings expand the genetic landscape of Perry syndrome, highlighting a novel pathogenic locus outside the CAP-GLY domain. DCTN1 screening should be considered in rapidly progressive parkinsonism with hypoventilation, especially in familial cases. Early diagnosis and intervention are crucial for prognosis.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-heterozygous-variant-in-dctn1-associated-with-perry-syndrome/