A Multi-State Structural Genomics Approach Enables Large-Scale, Mechanistic, and Context-Specific Classification of ABCC6 Genetic Variants Implicated in Calcification Diseases Article Swipe
Jessica B. Wagenknecht
,
Neshatul Haque
,
Salomao D. Jorge
,
Brian D. Ratnasinghe
,
Raúl Urrutia
,
William A. Gahl
,
Shira G. Ziegler
,
Michael T. Zimmermann
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.06.17.660194
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.06.17.660194
Purpose Genetic variation in ATP Binding Cassette Subfamily C Member 6 (ABCC6) can cause both pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI). Despite both diseases being rare, there are already 930 distinct missense variants in ABCC6 reported, 87% of which are of uncertain clinical significance (VUS). New approaches are needed to interpret and classify these VUS mechanistically. Methods We developed 3D protein models of ABCC6 in three functionally relevant conformations to calculate the structural effects of variants and identify 3D mutational hotspots. With this and additional functional information, we categorized variants in a mechanistic ontology based on which critical functions of ABCC6 they impact. We then compared PXE and GACI -associated variants. Results We identified two three-dimensional hotspots of pathogenic variants and six specific functions of ABCC6 which variants impact. From this, we propose a mechanism for pathogenicity for 41% of VUS according to their impacted function, 30 of which could be reclassified as Likely Pathogenic from our non-clinical data. Finally, we found slight differences between PXE and GACI-associated variants. Conclusion The mechanistic information we present will guide future research to better address calcification disorders and understand genetic variants. Further, our VUS reclassification will improve the diagnosis of ABCC6-driven diseases, shortening diagnostic odysseys. We believe that computational structural genomics approaches will soon take prominence in genomics data interpretation. Highlights Variant 3D hotspot detection and effect clustering, GACI and PXE Variant Comparison, consistent ability to (re)categorize known pathogenic variants, and population genetics differences.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.06.17.660194
- OA Status
- green
- References
- 55
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4411538717
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4411538717Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.06.17.660194Digital Object Identifier
- Title
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A Multi-State Structural Genomics Approach Enables Large-Scale, Mechanistic, and Context-Specific Classification of ABCC6 Genetic Variants Implicated in Calcification DiseasesWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-06-23Full publication date if available
- Authors
-
Jessica B. Wagenknecht, Neshatul Haque, Salomao D. Jorge, Brian D. Ratnasinghe, Raúl Urrutia, William A. Gahl, Shira G. Ziegler, Michael T. ZimmermannList of authors in order
- Landing page
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https://doi.org/10.1101/2025.06.17.660194Publisher landing page
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YesWhether a free full text is available
- OA status
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greenOpen access status per OpenAlex
- OA URL
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https://doi.org/10.1101/2025.06.17.660194Direct OA link when available
- Concepts
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Context (archaeology), Genomics, Scale (ratio), Calcification, Computational biology, State (computer science), Evolutionary biology, Biology, Computer science, Genome, Genetics, Medicine, Internal medicine, Gene, Geography, Cartography, Algorithm, PaleontologyTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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55Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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