{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T09:44:31Z","timestamp":1783503871239,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T00:00:00Z","timestamp":1625788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Osteogenesis imperfecta (OI) is a rare genetic disorder demonstrating considerable phenotypic and genetic heterogeneity. The extensively studied genotype\u2013phenotype correlation is a crucial issue for a reliable counseling, as the disease is recognized at increasingly earlier stages of life, including prenatal period. Based on population studies, clusters in <jats:italic>COL1A1<\/jats:italic> and <jats:italic>COL1A2<\/jats:italic> genes associated with the presence of glycine substitutions leading to fatal outcome have been distinguished and named as \u201clethal regions.\u201d Their localization corresponds to the ligand-binding sites responsible for extracellular interactions of collagen molecules, which could explain high mortality associated with mutations mapping to these regions. Although a number of non-lethal cases have been identified from the variants located in lethal clusters, the mortality rate of mutations has not been updated. An next generation sequencing analysis, using a custom gene panel of known and candidate OI genes, was performed on a group of 166 OI patients and revealed seven individuals with a causative mutations located in the lethal regions. Patients\u2019 age, ranging between 3 and 25 years, excluded the expected fatal outcome. The identification of non-lethal cases caused by mutations located in lethal domains prompted us to determine the actual mortality caused by glycine substitutions mapping to lethal clusters and evaluate the distribution of all lethal glycine mutations across collagen type I genes, based on records deposited in the OI Variant Database. Finally, we identified six glycine substitutions located in lethal regions of <jats:italic>COL1A1<\/jats:italic> and <jats:italic>COL1A2<\/jats:italic> genes, of which four are novel. The review of all mutations in the dedicated OI database, revealed 33 distinct glycine substitutions in two lethal domains of <jats:italic>COL1A1<\/jats:italic>, 26 of which have been associated with a fatal outcome. Similarly, 109 glycine substitutions have been identified in eight lethal clusters of <jats:italic>COL1A2<\/jats:italic>, of which 51 have been associated with a fatal manifestation. An analysis of all glycine substitutions leading to fatal phenotype, showed that their distribution along collagen type I genes is not regular, with 17% (26 out of 154) of mutations reported in <jats:italic>COL1A1<\/jats:italic> and 64% (51 out of 80) in <jats:italic>COL1A2<\/jats:italic> corresponding to localization of the lethal regions.<\/jats:p>","DOI":"10.3389\/fgene.2021.692978","type":"journal-article","created":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T05:31:02Z","timestamp":1625895062000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Novel Mutations Within Collagen Alpha1(I) and Alpha2(I) Ligand-Binding Sites, Broadening the Spectrum of Osteogenesis Imperfecta \u2013 Current Insights Into Collagen Type I Lethal Regions"],"prefix":"10.3389","volume":"12","author":[{"given":"Kinga","family":"Sa\u0142aci\u0144ska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwona","family":"Pinkier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Rutkowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danuta","family":"Chlebna-Sok\u00f3\u0142","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u017cbieta","family":"Jakubowska-Pietkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Micha\u0142us","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0141ukasz","family":"K\u0119pczy\u0144ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Salachna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Jamsheer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Bukowska-Olech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilona","family":"Jaszczuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucjusz","family":"Jakubowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Gach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1097\/GIM.0b013e3181a1ff7b","article-title":"Osteogenesis imperfecta: recent findings shed new light on this once well-understood condition.","volume":"11","author":"Basel","year":"2009","journal-title":"Genet. 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