{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:48:13Z","timestamp":1790801293610,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Inherited retinal dystrophies (IRDs) are clinically and genetically heterogeneous disorders. Most IRDs follow a monogenic inheritance pattern. However, an increasing number of unresolved cases suggest the possible contribution of oligogenic or digenic mechanisms. Here, we report two ultra-rare missense variants\u2014AIPL1 R302L and BBS2 P134R\u2014that co-segregate with early-onset nonsyndromic retinal degeneration in affected individuals from a non-consanguineous family. We performed a multi-level computational investigation to assess whether these variants may act through a convergent pathogenic mechanism. Using AlphaFold2-predicted structures, we modeled both wild-type and mutant proteins, introduced point mutations, and performed energy minimization and validation. FoldX, DynaMut2, and DUET all predicted destabilizing effects at the variant sites, corroborated by local disruption of secondary structure and altered surface electrostatics. Comparative docking (via HDOCK and ClusPro) identified a putative interaction interface between the TPR domain of AIPL1 and the \u03b2-sheet face of BBS2. This interface was destabilized in the double-mutant model. At the systems level, transcriptomic profiling confirmed co-expression of AIPL1 and BBS2 in human retina and fetal eye, while functional enrichment analysis highlighted overlapping involvement in ciliary and proteostasis pathways. Network propagation suggested that the two proteins may converge on shared interactors relevant to photoreceptor maintenance. Collectively, these in silico results provide structural and systems-level support for a candidate digenic mechanism involving AIPL1 and BBS2. While experimental validation remains necessary, our study proposes a testable mechanistic hypothesis and underscores the value of computational approaches in uncovering complex genetic contributions to IRDs.<\/jats:p>","DOI":"10.3390\/ijms26199430","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T13:30:03Z","timestamp":1758893403000},"page":"9430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Computational Evidence for Digenic Contribution of AIPL1 and BBS2 Rare Variants in Inherited Retinal Dystrophy"],"prefix":"10.3390","volume":"26","author":[{"given":"Simona","family":"Alibrandi","sequence":"first","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"},{"name":"Department of Biomolecular Strategies, Genetics, Cutting-Edge Therapies, I.E.ME.S.T., Via Michele Miraglia 20, 90139 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-1693","authenticated-orcid":false,"given":"Concetta","family":"Scimone","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Abate","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8467-1714","authenticated-orcid":false,"given":"Sergio Zaccaria","family":"Scalinci","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Bologna, 40121 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonina","family":"Sidoti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5292-426X","authenticated-orcid":false,"given":"Luigi","family":"Donato","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"},{"name":"Department of Biomolecular Strategies, Genetics, Cutting-Edge Therapies, I.E.ME.S.T., Via Michele Miraglia 20, 90139 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nebbioso, M., Artico, M., Gharbiya, M., Mannocci, A., Limoli, P.G., Iannetta, D., and Donato, L. 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