{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T06:37:07Z","timestamp":1772692627673,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004008","name":"Istituto Superiore di Sanit\u00e0","doi-asserted-by":"crossref","award":["ISS20-5656c541c257"],"award-info":[{"award-number":["ISS20-5656c541c257"]}],"id":[{"id":"10.13039\/501100004008","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004008","name":"Istituto Superiore di Sanit\u00e0","doi-asserted-by":"crossref","award":["ISS20-2e15b898baf0"],"award-info":[{"award-number":["ISS20-2e15b898baf0"]}],"id":[{"id":"10.13039\/501100004008","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RF-2021-12374963"],"award-info":[{"award-number":["RF-2021-12374963"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Retinitis pigmentosa (RP) comprises a heterogeneous group of inherited retinal dystrophies characterized by the progressive degeneration of photoreceptors, leading to night blindness and gradual loss of peripheral vision. RP is characterized by a substantial genetic heterogeneity, with more than 85 genes implicated across autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have identified mutations in the ARL3 gene as a causative factor in both syndromic and non-syndromic forms of RP, including autosomal dominant and recessive cases. ARL3 encodes a small GTPase that plays a crucial role in intracellular trafficking, particularly within photoreceptors. This process is critical for maintaining ciliary function and phototransduction. Here, we investigate the pathogenic mechanisms of the ARL3 c.199G&gt;C (p.Asp67His) variant identified in individuals from a four-generation family. We show that mutant ARL3 disrupts normal protein expression and affects ciliogenesis. Clinically affected individuals showed a non-syndromic retinal degenerative RP phenotype, with marked intrafamilial heterogeneity, ranging from extensive retinal atrophy to the absence of clinical manifestation, independent of age. This report highlights the incomplete penetrance and variable expressivity associated with the ARL3 variant and emphasizes the value of combining molecular diagnostics with functional validation to expedite molecular diagnosis.<\/jats:p>","DOI":"10.3390\/ijms27052368","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T16:18:45Z","timestamp":1772554725000},"page":"2368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Heterozygous ARL3 Variant in Non-Syndromic Retinitis Pigmentosa: Clinical and Functional Characterization"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0415-3285","authenticated-orcid":false,"given":"Emilia","family":"Stellacci","sequence":"first","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5563-1243","authenticated-orcid":false,"given":"Lucia","family":"Ziccardi","sequence":"additional","affiliation":[{"name":"IRCCS-Fondazione Bietti, Via Livenza 1, 00198 Rome, Italy"},{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, Via De Sanctis 1, 86100 Campobasso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1556-4998","authenticated-orcid":false,"given":"Alessandro","family":"Bruselles","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4395-0818","authenticated-orcid":false,"given":"Carmen","family":"Dell\u2019Aquila","sequence":"additional","affiliation":[{"name":"IRCCS-Fondazione Bietti, Via Livenza 1, 00198 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7384-6212","authenticated-orcid":false,"given":"Luca","family":"Mignini","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Viale di San Paolo 15, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4766-7753","authenticated-orcid":false,"given":"Marcello","family":"Niceta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Viale di San Paolo 15, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0604-1796","authenticated-orcid":false,"given":"Luigi","family":"Chiriatti","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Viale di San Paolo 15, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4584-0663","authenticated-orcid":false,"given":"Mattia","family":"Carvetta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Viale di San Paolo 15, 00146 Rome, Italy"},{"name":"Department of Biochemical Sciences \u201cAlessandro Rossi Fanelli\u201d, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0292-6862","authenticated-orcid":false,"given":"Erika","family":"Zara","sequence":"additional","affiliation":[{"name":"CNMR, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6103-3559","authenticated-orcid":false,"given":"Alessandro","family":"Leone","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"},{"name":"Department of Humanities, Law and Economics, Telematic University Leonardo da Vinci, UNIDAV, 66010 Torrevecchia Teatina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3601-176X","authenticated-orcid":false,"given":"Serena","family":"Cecchetti","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Unit\u2014Core Facilities, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7851-9409","authenticated-orcid":false,"given":"Simona","family":"Coppola","sequence":"additional","affiliation":[{"name":"CNMR, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Parisi","sequence":"additional","affiliation":[{"name":"IRCCS-Fondazione Bietti, Via Livenza 1, 00198 Rome, Italy"},{"name":"Departmental Faculty of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, Via di Sant\u2019Alessandro 8\/30, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Viale di San Paolo 15, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viviana","family":"Cordeddu","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ben-Yosef, T. (2022). Inherited Retinal Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113467"},{"key":"ref_2","unstructured":"Fahim, A.T., Daiger, S.P., and Weleber, R.G. (2023). Nonsyndromic Retinitis Pigmentosa Overview. GeneReviews\u00ae, University of Washington. 2000 Aug 4 [Updated 2023]."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ratnapriya, R., Jacobson, S.G., Cideciyan, A.V., English, M.A., Roman, A.J., Sumaroka, A., Sheplock, R., and Swaroop, A. (2021). A Novel ARL3 Gene Mutation Associated with Autosomal Dominant Retinal Degeneration. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.720782"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1096\/fba.2023-00138","article-title":"Mitochondrial Functional Impairment in ARL3 -mutation Related Rod-cone Dystrophy","volume":"6","author":"Zhang","year":"2024","journal-title":"FASEB BioAdv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1093\/hmg\/ddaf029","article-title":"A Novel Recurrent ARL3 Variant c.209G>A p.(Gly70Glu) Causes Variable Non-Syndromic Dominant Retinal Dystrophy with Defective Lipidated Protein Transport in Human Retinal Stem Cell Models","volume":"34","author":"Vaclavik","year":"2025","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1093\/hmg\/ddw077","article-title":"ARL3 Regulates Trafficking of Prenylated Phototransduction Proteins to the Rod Outer Segment","volume":"25","author":"Wright","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4811","DOI":"10.1167\/iovs.19-27263","article-title":"Homozygous Variant in ARL3 Causes Autosomal Recessive Cone Rod Dystrophy","volume":"60","author":"Sheikh","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1080\/21541248.2016.1224454","article-title":"Sorting of Lipidated Cargo by the Arl2\/Arl3 System","volume":"7","author":"Fansa","year":"2016","journal-title":"Small GTPases"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/nn.2835","article-title":"UNC119 Is Required for G Protein Trafficking in Sensory Neurons","volume":"14","author":"Zhang","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e80533","DOI":"10.7554\/eLife.80533","article-title":"Disrupting the Ciliary Gradient of Active Arl3 Affects Rod Photoreceptor Nuclear Migration","volume":"12","author":"Travis","year":"2023","journal-title":"eLife"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19691","DOI":"10.1073\/pnas.1210916109","article-title":"ARL13B, PDE6D, and CEP164 Form a Functional Network for INPP5E Ciliary Targeting","volume":"109","author":"Humbert","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4085","DOI":"10.1038\/emboj.2012.257","article-title":"Structural Basis for Arl3-Specific Release of Myristoylated Ciliary Cargo from UNC119: Ciliary Targeting of Myristoylated Cargo","volume":"31","author":"Ismail","year":"2012","journal-title":"EMBO J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nsmb.1396","article-title":"The Retinitis Pigmentosa 2 Gene Product Is a GTPase-Activating Protein for Arf-like 3","volume":"15","author":"Veltel","year":"2008","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1093\/hmg\/11.24.3065","article-title":"Localization in the Human Retina of the X-Linked Retinitis Pigmentosa Protein RP2, Its Homologue Cofactor C and the RP2 Interacting Protein Arl3","volume":"11","author":"Grayson","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.ajhg.2018.08.015","article-title":"ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition","volume":"103","author":"Alkanderi","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","first-page":"118","article-title":"Joubert Syndrome: Molecular Basis and Treatment","volume":"26","author":"Spahiu","year":"2023","journal-title":"J. Mother Child"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Powell, L., Barroso-Gil, M., Clowry, G.J., Devlin, L.A., Molinari, E., Ramsbottom, S.A., Miles, C.G., and Sayer, J.A. (2020). Expression Patterns of Ciliopathy Genes ARL3 and CEP120 Reveal Roles in Multisystem Development. BMC Dev. Biol., 20.","DOI":"10.1186\/s12861-020-00231-3"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1080\/13816810.2019.1586965","article-title":"Dominant ARL3-Related Retinitis Pigmentosa","volume":"40","author":"Holtan","year":"2019","journal-title":"Ophthalmic Genet."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Strom, S.P., Clark, M.J., Martinez, A., Garcia, S., Abelazeem, A.A., Matynia, A., Parikh, S., Sullivan, L.S., Bowne, S.J., and Daiger, S.P. (2016). De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150944"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fu, L., Li, Y., Yao, S., Guo, Q., You, Y., Zhu, X., and Lei, B. (2021). Autosomal Recessive Rod-Cone Dystrophy Associated with Compound Heterozygous Variants in ARL3 Gene. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.635424"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1186\/s13287-023-03564-5","article-title":"Application of Patient-Derived Induced Pluripotent Stem Cells and Organoids in Inherited Retinal Diseases","volume":"14","author":"Liang","year":"2023","journal-title":"Stem Cell Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7142","DOI":"10.1074\/jbc.M115.710954","article-title":"Arf-like protein 3 (ARL3) regulates protein trafficking and ciliogenesis in mouse photoreceptors","volume":"291","author":"Wu","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1093\/jb\/mvae057","article-title":"Ciliary length variations impact cilia-mediated signaling and biological responses","volume":"176","author":"Kobayashi","year":"2024","journal-title":"J. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yam\u00e9ogo, P., Majeau, N., Happi Mbakam, C., and Tremblay, J.P. (2023). Small-molecule inhibitors of proteasome increase CjCas9 protein stability. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0280353"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Lei, Z., Wang, J., Zhang, L., and Liu, C.H. (2021). Ubiquitination-dependent regulation of small GTPases in membrane trafficking: From cell biology to human diseases. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.688352"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kingdom, R., and Wright, C.F. (2022). Incomplete penetrance and variable expressivity: From clinical studies to population cohorts. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.920390"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Al-Khuzaei, S., Shah, M., Reginald, A., Baba, E., Shanks, M., Clouston, P., MacLaren, R., Halford, S., De Silva, S., and Downes, S.M. (2025). Genotype\u2013phenotype correlations in PRPH2 retinopathies: A comprehensive analysis of 36 patients from the Oxford Eye Hospital, UK. Genes, 16.","DOI":"10.3390\/genes16091016"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1167\/iovs.65.5.22","article-title":"Retinal Dystrophies Associated with Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients","volume":"65","author":"Thompson","year":"2024","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1186\/s12967-019-2080-3","article-title":"Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology","volume":"17","author":"Frecer","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"jcs264191","DOI":"10.1242\/jcs.264191","article-title":"Morphological reprogramming of primary cilia length mitigates the fibrotic phenotype in fibroblasts across diverse fibrotic conditions","volume":"138","author":"Verma","year":"2025","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12470","DOI":"10.1038\/s41598-024-60298-x","article-title":"Primary cilia suppress the fibrotic activity of atrial fibroblasts from patients with atrial fibrillation in vitro","volume":"14","author":"Kawasaki","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1093\/hmg\/ddx143","article-title":"Arl3 and RP2 regulate the trafficking of ciliary tip kinesins","volume":"26","author":"Schwarz","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e11859","DOI":"10.7554\/eLife.11859","article-title":"A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins","volume":"4","author":"Gotthardt","year":"2015","journal-title":"eLife"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s10633-022-09872-0","article-title":"ISCEV Standard for Full-Field Clinical Electroretinography (2022 Update)","volume":"144","author":"Robson","year":"2022","journal-title":"Doc. Ophthalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10633-020-09812-w","article-title":"ISCEV standard for clinical multifocal electroretinography (mfERG) (2021 update)","volume":"142","author":"Hoffmann","year":"2021","journal-title":"Doc. Ophthalmol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3572","DOI":"10.1093\/bioinformatics\/bty304","article-title":"AnnotSV: An Integrated Tool for Structural Variations Annotation","volume":"34","author":"Geoffroy","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1016\/j.ajhg.2021.09.007","article-title":"SPRED2 Loss-of-Function Causes a Recessive Noonan Syndrome-like Phenotype","volume":"108","author":"Motta","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ajhg.2021.01.015","article-title":"SPEN Haploinsufficiency Causes a Neurodevelopmental Disorder Overlapping Proximal 1p36 Deletion Syndrome with an Episignature of X Chromosomes in Females","volume":"108","author":"Radio","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A General Framework for Estimating the Relative Pathogenicity of Human Genetic Variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP Eliminates a Majority of Variants of Uncertain Significance in Clinical Exomes at High Sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the As-sociation for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines","volume":"100","author":"Li","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"i333","DOI":"10.1093\/bioinformatics\/bts378","article-title":"DELLY: Structural Variant Discovery by Integrated Paired-End and Split-Read Analysis","volume":"28","author":"Rausch","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.ajhg.2016.07.005","article-title":"A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease","volume":"99","author":"Smedley","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera: A Visualization System for Exploratory Research and Analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_46","first-page":"10147","article-title":"Prediction of water and metal binding sites and their affinities by using the Fold-X force field","volume":"102","author":"Schymkowitz","year":"2005","journal-title":"Biophys. Comput. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Ziccardi, L., Niceta, M., Stellacci, E., Ciolfi, A., Tatti, M., Bruselles, A., Mancini, C., Barbano, L., Cecchetti, S., and Costanzo, E. (2022). Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314656"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T05:18:39Z","timestamp":1772687919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,3]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27052368"],"URL":"https:\/\/doi.org\/10.3390\/ijms27052368","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,3]]}}}