{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T02:22:39Z","timestamp":1778034159228,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["23-24-00555"],"award-info":[{"award-number":["23-24-00555"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bruck syndrome is a rare autosomal recessive disorder characterized by increased bone fragility and joint contractures similar to those in arthrogryposis and is known to be associated with mutations in the FKBP10 (FKBP prolyl isomerase 10) and PLOD2 (Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 2) genes. These genes encode endoplasmic reticulum proteins that play an important role in the biosynthesis of type I collagen, which in turn affects the structure and strength of connective tissues and bones in the body. Mutations are associated with disturbances in both the primary collagen chain and its post-translational formation, but the mechanism by which mutations lead to Bruck syndrome phenotypes has not been determined, not only because of the small number of patients who come to the attention of researchers but also because of the lack of disease models. In our work, we investigated the cellular effects of two forms of the wild-type PLOD2 gene, as well as the PLOD2 gene with homozygous mutation c.1885A&gt;G (p.Thr629Ala). The synthesized genetic constructs were transfected into HEK293 cell line and human skin fibroblasts (DF2 line). The localization of PLOD2 protein in cells and the effects caused by the expression of different isoforms\u2014long, short, and long with mutation\u2014were analyzed. In addition, the results of the transcriptome analysis of a patient with Bruck syndrome, in whom this mutation was detected, are presented.<\/jats:p>","DOI":"10.3390\/ijms252413379","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T05:55:45Z","timestamp":1734069345000},"page":"13379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cellular and Molecular Effects of the Bruck Syndrome-Associated Mutation in the PLOD2 Gene"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3761-3014","authenticated-orcid":false,"given":"Olga I.","family":"Bolshakova","sequence":"first","affiliation":[{"name":"Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre \u00abKurchatov Institute\u00bb, 188300 Gatchina, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evgenia M.","family":"Latypova","sequence":"additional","affiliation":[{"name":"Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre \u00abKurchatov Institute\u00bb, 188300 Gatchina, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3564-1698","authenticated-orcid":false,"given":"Artem E.","family":"Komissarov","sequence":"additional","affiliation":[{"name":"Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre \u00abKurchatov Institute\u00bb, 188300 Gatchina, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra D.","family":"Slobodina","sequence":"additional","affiliation":[{"name":"Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre \u00abKurchatov Institute\u00bb, 188300 Gatchina, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-6722","authenticated-orcid":false,"given":"Elena V.","family":"Ryabova","sequence":"additional","affiliation":[{"name":"Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre \u00abKurchatov Institute\u00bb, 188300 Gatchina, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3287-4709","authenticated-orcid":false,"given":"Elena Yu.","family":"Varfolomeeva","sequence":"additional","affiliation":[{"name":"Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre \u00abKurchatov Institute\u00bb, 188300 Gatchina, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga E.","family":"Agranovich","sequence":"additional","affiliation":[{"name":"Turner National Medical Research Center for Children\u2019s Orthopedics and Trauma Surgery, 196603 Saint Petersurg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9992-8906","authenticated-orcid":false,"given":"Sergey F.","family":"Batkin","sequence":"additional","affiliation":[{"name":"Turner National Medical Research Center for Children\u2019s Orthopedics and Trauma Surgery, 196603 Saint Petersurg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3943-7504","authenticated-orcid":false,"given":"Svetlana V.","family":"Sarantseva","sequence":"additional","affiliation":[{"name":"Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre \u00abKurchatov Institute\u00bb, 188300 Gatchina, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1179\/146532809X440798","article-title":"Bruck syndrome: Osteogenesis imperfecta and arthrogryposis multiplex congenita","volume":"29","author":"Ozcan","year":"2009","journal-title":"Ann. Trop. Paediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/pd.801","article-title":"Prenatal diagnosis of Bruck syndrome","volume":"25","author":"Berg","year":"2005","journal-title":"Prenat. Diagn."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115047","DOI":"10.1016\/j.bone.2019.115047","article-title":"Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation","volume":"130","author":"Mumm","year":"2020","journal-title":"Bone"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1002\/humu.22133","article-title":"Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome--osteogenesis imperfecta phenotypic spectrum","volume":"33","author":"Temtamy","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1002\/jbmr.2977","article-title":"Loss of Type I Collagen Telopeptide Lysyl Hydroxylation Causes Musculoskeletal Abnormalities in a Zebrafish Model of Bruck Syndrome","volume":"31","author":"Gistelinck","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_6","first-page":"115","article-title":"Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2","volume":"131","author":"Alanay","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_7","first-page":"8014038","article-title":"Orthopedic Manifestations of Bruck Syndrome: A Case Series with Intermediate to Long-term Follow-Up","volume":"2019","author":"Santana","year":"2019","journal-title":"Case Rep. Orthop."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, R.L., Ruan, D.D., Hu, Y.N., Gan, Y.M., Lin, X.F., Fang, Z.T., Liao, L.S., Tang, F.Q., He, W.B., and Luo, J.W. (2022). Genetic Analysis and Functional Study of a Pedigree With Bruck Syndrome Caused by PLOD2 Variant. Front. Pediatr., 10.","DOI":"10.3389\/fped.2022.878172"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"30917","DOI":"10.1074\/jbc.M109.021238","article-title":"Missense mutations that cause Bruck syndrome affect enzymatic activity, folding, and oligomerization of lysyl hydroxylase 2","volume":"284","author":"Hyry","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1002\/jbmr.3348","article-title":"Expanding the Clinical Spectrum of Phenotypes Caused by Pathogenic Variants in PLOD2","volume":"33","author":"Leal","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1007\/s00223-017-0360-6","article-title":"Novel Mutations in PLOD2 Cause Rare Bruck Syndrome","volume":"102","author":"Lv","year":"2018","journal-title":"Calcif. Tissue Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"537","DOI":"10.17816\/PTORS569365","article-title":"Phenotypic variability in children with Bruck syndrome type 2: Clinical cases","volume":"11","author":"Trofimova","year":"2023","journal-title":"Pediatr. Traumatol. Orthop. Reconstr. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhou, P., Liu, Y., Lv, F., Nie, M., Jiang, Y., Wang, O., Xia, W., Xing, X., and Li, M. (2014). Novel mutations in FKBP10 and PLOD2 cause rare Bruck syndrome in Chinese patients. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107594"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"40967","DOI":"10.1074\/jbc.M307380200","article-title":"Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis","volume":"278","author":"Zuurmond","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6831","DOI":"10.1074\/jbc.272.11.6831","article-title":"Cloning and characterization of a novel human lysyl hydroxylase isoform highly expressed in pancreas and muscle","volume":"272","author":"Valtavaara","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0945-053X(99)00013-X","article-title":"Tissue specificity of a new splice form of the human lysyl hydroxylase 2 gene","volume":"18","author":"Yeowell","year":"1999","journal-title":"Matrix Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.matbio.2004.11.002","article-title":"Tissue-specific expression and regulation of the alternatively-spliced forms of lysyl hydroxylase 2 (LH2) in human kidney cells and skin fibroblasts","volume":"23","author":"Walker","year":"2005","journal-title":"Matrix Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.bbrc.2019.09.081","article-title":"An in vitro model to evaluate the properties of matrices produced by fibroblasts from osteogenesis imperfecta and Ehlers-Danlos Syndrome patients","volume":"521","author":"Micha","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.7150\/jca.41828","article-title":"PLOD2 increases resistance of gastric cancer cells to 5-fluorouracil by upregulating BCRP and inhibiting apoptosis","volume":"11","author":"Wang","year":"2020","journal-title":"J. Cancer"},{"key":"ref_20","first-page":"102","article-title":"Expression of PLOD2 in esophageal squamous cell carcinoma and its correlation with invasion and metastasis","volume":"48","author":"Di","year":"2019","journal-title":"Zhonghua Bing Li Xue Za Zhi"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e3143","DOI":"10.1038\/cddis.2017.553","article-title":"PLOD2 regulated by transcription factor FOXA1 promotes metastasis in NSCLC","volume":"8","author":"Du","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1002\/art.27315","article-title":"Fox-2 protein regulates the alternative splicing of scleroderma-associated lysyl hydroxylase 2 messenger RNA","volume":"62","author":"Seth","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mo, W.C., Zhang, Z.J., Wang, D.L., Liu, Y., Bartlett, P.F., and He, R.Q. (2016). Shielding of the Geomagnetic Field Alters Actin Assembly and Inhibits Cell Motility in Human Neuroblastoma Cells. Sci. Rep., 6, Erratum in Sci Rep. 2016, 6, 32055.","DOI":"10.1038\/srep22624"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.3892\/or.2017.5538","article-title":"The downstream of tyrosine kinase 7 is reduced in lung cancer and is associated with poor survival of patients with lung cancer","volume":"37","author":"Chen","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1111\/j.1600-6143.2008.02322.x","article-title":"Effects of mycophenolic acid on human fibroblast proliferation, migration and adhesion in vitro and in vivo","volume":"8","author":"Morath","year":"2008","journal-title":"Am. J. Transplant."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Valdivia, A., Avalos, A.M., and Leyton, L. (2023). Thy-1 (CD90)-regulated cell adhesion and migration of mesenchymal cells: Insights into adhesomes, mechanical forces, and signaling pathways. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1221306"},{"key":"ref_27","first-page":"3143","article-title":"Extracellular matrix promotes proliferation, migration and adhesion of airway smooth muscle cells in a rat model of chronic obstructive pulmonary disease via upregulation of the PI3K\/AKT signaling pathway","volume":"18","author":"Wang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5925","DOI":"10.1074\/jbc.M113.516617","article-title":"A 130-kDa protein 4.1B regulates cell adhesion, spreading, and migration of mouse embryo fibroblasts by influencing actin cytoskeleton organization","volume":"289","author":"Wang","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1093\/glycob\/cwr020","article-title":"Polysialylation promotes neural cell adhesion molecule-mediated cell migration in a fibroblast growth factor receptor-dependent manner, but independent of adhesion capability","volume":"21","author":"Li","year":"2011","journal-title":"Glycobiology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bokhobza, A., Ziental-Gelus, N., Allart, L., Iamshanova, O., and Vanden Abeele, F. (2021). Impact of SOCE Abolition by ORAI1 Knockout on the Proliferation, Adhesion, and Migration of HEK-293 Cells. Cells, 10.","DOI":"10.3390\/cells10113016"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100850","DOI":"10.1016\/j.isci.2020.100850","article-title":"PLOD2 Is Essential to Functional Activation of Integrin \u03b21 for Invasion\/Metastasis in Head and Neck Squamous Cell Carcinomas","volume":"23","author":"Ueki","year":"2020","journal-title":"iScience"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kre\u00dfe, N., Schr\u00f6der, H., Stein, K.P., Wilkens, L., Mawrin, C., Sandalcioglu, I.E., and Dumitru, C.A. (2022). PLOD2 Is a Prognostic Marker in Glioblastoma That Modulates the Immune Microenvironment and Tumor Progression. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116037"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sun, Y., Wang, S., Zhang, X., Wu, Z., Li, Z., Ding, Z., Huang, X., Chen, S., Jing, Y., and Zhang, X. (2021). Identification and Validation of PLOD2 as an Adverse Prognostic Biomarker for Oral Squamous Cell Carcinoma. Biomolecules, 11.","DOI":"10.3390\/biom11121842"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"23401","DOI":"10.18632\/oncotarget.15581","article-title":"Procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 promotes hypoxia-induced glioma migration and invasion","volume":"8","author":"Xu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Cao, C., Ma, Q., Huang, X., Li, A., Liu, J., Ye, J., and Gui, Y. (2021). Targeted Demethylation of the PLOD2 mRNA Inhibits the Proliferation and Migration of Renal Cell Carcinoma. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.675683"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41947","DOI":"10.18632\/oncotarget.16710","article-title":"Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K\/Akt signaling in glioma","volume":"8","author":"Song","year":"2017","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Xu, Q., Kong, N., Zhao, Y., Wu, Q., Wang, X., Xun, X., and Gao, P. (2022). Pan-Cancer Analyses Reveal Oncogenic and Immunological Role of PLOD2. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.864655"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1093\/hmg\/ddac254","article-title":"Dynamics and variability of transcriptomic dysregulation in congenital myotonic dystrophy during pediatric development","volume":"32","author":"Hale","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2201273","DOI":"10.1002\/advs.202201273","article-title":"ER, Mitochondria, and ISR Regulation by mt-HSP70 and ATF5 on Procollagen Misfolding in Osteoblasts","volume":"9","author":"Gorrell","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1002\/ajmg.a.62188","article-title":"MYH1 is a candidate gene for recurrent rhabdomyolysis in humans","volume":"185","author":"Alsaif","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3233\/NPM-210780","article-title":"Novel mutation in the MYH2 gene in a symptomatic neonate with a hereditary myosin myopathy","volume":"15","author":"Oatmen","year":"2022","journal-title":"J. Neonatal Perinat. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1086\/342380","article-title":"Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin","volume":"71","author":"Hackman","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.nmd.2006.04.009","article-title":"Myotilinopathy in a family with late onset myopathy","volume":"16","author":"Talvinen","year":"2006","journal-title":"Neuromuscul. Disord."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Favara, D.M., Liebscher, I., Jazayeri, A., Nambiar, M., Sheldon, H., Banham, A.H., and Harris, A.L. (2021). Elevated expression of the adhesion GPCR ADGRL4\/ELTD1 promotes endothelial sprouting angiogenesis without activating canonical GPCR signalling. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-85408-x"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1093\/bioinformatics\/btac166","article-title":"Analysing high-throughput sequencing data in Python with HTSeq 2.0","volume":"38","author":"Putri","year":"2022","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13379\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:54:22Z","timestamp":1760115262000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13379"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,13]]},"references-count":50,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252413379"],"URL":"https:\/\/doi.org\/10.3390\/ijms252413379","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,13]]}}}