VPS16 – Dystonic Disorder

This summary synthesizes multiple lines of evidence supporting an association between VPS16 (HGNC:14584) and dystonic disorder (MONDO_0003441). Several independent case reports have identified VPS16 variants in patients manifesting clinical features consistent with dystonia. In one report, a heterozygous splice‐site variant disrupting mRNA processing was characterized at the transcript level (PMID:37226038). Furthermore, a recurrent nonsense variant, c.1513C>T (p.Arg505Ter), has been observed in familial cases with early‐onset dystonia and segregates with disease (PMID:39055541), reinforcing its clinical relevance.

Genetic evidence indicates an autosomal dominant mode of inheritance for most VPS16‐associated dystonia cases. Multiple studies report heterozygous loss-of-function and splice variants in unrelated probands, with segregation observed in affected family members (PMID:27174565). Additionally, large-scale multi-patient analyses have shown an enrichment of VPS16 loss-of-function variants in dystonia cohorts when compared with control populations (PMID:34901436). These findings underscore the broad variant spectrum, including missense, nonsense, and frameshift mutations, converging on a deleterious effect on VPS16 function.

The genetic evidence is complementary to functional studies that elucidate the pathogenic mechanism. In vitro assays have demonstrated that mutations in VPS16 reduce the activity of the mRNA decapping enzyme, thereby stabilizing mRNAs in a way that is consistent with a loss-of-function mechanism (PMID:10523645). Structural studies further support this model by showing that VPS16 is critical for recruiting Vps33A to the HOPS complex, with mutations disrupting this interaction and impairing endosome-lysosome fusion (PMID:23901104).

Across the reported studies, the integration of segregation data, a diverse variant spectrum, and robust experimental validation leads to a coherent narrative that VPS16 disruption contributes significantly to the dystonic phenotype. Although some reports describe autosomal recessive forms, the preponderance of heterozygous pathogenic variants suggests that autosomal dominant inheritance is most common. This consolidated evidence provides high-confidence support for the gene–disease association and offers a strong basis for its incorporation into clinical diagnostic workflows.

Given the convergence of genetic and experimental evidence, the association between VPS16 and dystonic disorder is well substantiated. The multiple independent observations, functional assays, and segregation analyses provide compelling support for a strong gene-disease relationship. This information is thus valuable for diagnostic decision-making, commercial use in genetic testing panels, and further scientific publications.

Key take‑home sentence: VPS16 loss-of-function variants represent a robust genetic contributor to dystonic disorder, with integrated clinical and experimental data supporting their diagnostic utility.

References

• Neurogenetics • 2023 • Aberrant Splicing Caused by a Novel VPS16 Variant Linked to Dystonia Type 30 PMID:37226038
• Rheumatology advances in practice • 2024 • Familial Mediterranean Fever Gene Variations Could Trigger VPS16-associated Early-Onset Dystonia and Diabetes Mellitus: Clinical Identification of a Family with MEFV and VPS16 Genetic Variation Association PMID:39055541
• Scientific reports • 2016 • Homozygous Mutation of VPS16 Gene is Responsible for an Autosomal Recessive Adolescent-Onset Primary Dystonia PMID:27174565
• Neurology. Genetics • 2022 • Transcript-Specific Loss-of-Function Variants in VPS16 Are Enriched in Patients With Dystonia PMID:34901436
• Molecular and cellular biology • 1999 • Mutations in VPS16 and MRT1 Stabilize mRNAs by Activating an Inhibitor of the Decapping Enzyme PMID:10523645
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Structural Basis of Vps33A Recruitment to the Human HOPS Complex by Vps16 PMID:23901104

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