{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T10:38:43Z","timestamp":1770460723855,"version":"3.49.0"},"reference-count":86,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004252","name":"Qatar University","doi-asserted-by":"publisher","award":["QUST-2-CHS-2020- 12"],"award-info":[{"award-number":["QUST-2-CHS-2020- 12"]}],"id":[{"id":"10.13039\/501100004252","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1\u2013242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.<\/jats:p>","DOI":"10.3390\/molecules25235543","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T22:00:33Z","timestamp":1606428033000},"page":"5543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6639-3746","authenticated-orcid":false,"given":"Udhaya Kumar","family":"S.","sequence":"first","affiliation":[{"name":"School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srivarshini","family":"Sankar","sequence":"additional","affiliation":[{"name":"School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salma","family":"Younes","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health and Sciences, Qatar University, QU Health, Doha 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thirumal Kumar","family":"D.","sequence":"additional","affiliation":[{"name":"School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muneera Naseer","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health and Sciences, Qatar University, QU Health, Doha 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah Samer","family":"Okashah","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health and Sciences, Qatar University, QU Health, Doha 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9747-3984","authenticated-orcid":false,"given":"Balu","family":"Kamaraj","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Technology, College of Applied Medical Sciences in Jubail, Imam Abdulrahman Bin Faisal University, Jubail 35816, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9332-7082","authenticated-orcid":false,"given":"Abeer Mohammed","family":"Al-Subaie","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George Priya Doss","family":"C.","sequence":"additional","affiliation":[{"name":"School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8838-6638","authenticated-orcid":false,"given":"Hatem","family":"Zayed","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health and Sciences, Qatar University, QU Health, Doha 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/35052082","article-title":"Filamins as integrators of cell mechanics and signaling","volume":"2","author":"Stossel","year":"2001","journal-title":"Nat. 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