{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:20:29Z","timestamp":1792113629368,"version":"4.4.0"},"reference-count":28,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"School of Dentistry, Seoul National University"},{"id":[{"id":"https:\/\/ror.org\/04h9pn542","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIDCR\/NIH","doi-asserted-by":"publisher","award":["DE015846"],"award-info":[{"award-number":["DE015846"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"award":["DE015846"],"award-info":[{"award-number":["DE015846"]}],"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Amelogenesis imperfecta (AI) is a heterogeneous group of rare hereditary conditions mainly affecting the quantity and\/or quality of tooth enamel. Its phenotypic expression is diverse, as is the mutational spectrum of the AI-causing genes and mutations. Integrins are cell-surface receptors that mediate adhesion between cells and between cells and the extracellular matrix. Among these, mutations in integrin \u03b1v\u03b26 have been shown to cause AI; however, phenotypic variation exists between the knockout mouse model and human cases, as well as among different human AI families. Methods: We recruited AI families and performed mutational analysis using whole exome sequencing. Results: We identified compound heterozygous ITGB6 mutations in two families. In Family 1, a paternally transmitted nonsense mutation (NM_000888.5: c.1060C&gt;T, p.(Gln354*)) and a maternally transmitted missense mutation (NM_000888.5: c.2312A&gt;G, p.(Asn771Ser)) were identified; in Family 2, a paternal missense mutation (NM_000888.5: c.1693T&gt;C, p.(Cys565Arg)) and a maternal frameshift mutation (NM_000888.5: c.2091delC, p.(Asn698Metfs*13)) were identified, each causing AI in the respective proband. Both probands exhibited generalized hypoplastic and hypomineralized AI, but no other extraoral symptoms. Conclusions: This report will not only expand the known mutational spectrum of the ITGB6 gene but also provide evidence for the genotype\u2013phenotype correlations, thereby improving our understanding of the functional role of ITGB6 during amelogenesis.<\/jats:p>","DOI":"10.3390\/genes17040431","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T07:25:12Z","timestamp":1775633112000},"page":"431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel ITGB6 Mutations Causing Amelogenesis Imperfecta"],"prefix":"10.3390","volume":"17","author":[{"given":"Hyemin","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Pediatric Dentistry, School of Dentistry & Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soojin","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry, School of Dentistry & Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyuntae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry, School of Dentistry & Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7192-6105","authenticated-orcid":false,"given":"James P.","family":"Simmer","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9294-0248","authenticated-orcid":false,"given":"Jan C.-C.","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9399-2197","authenticated-orcid":false,"given":"Jung-Wook","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry, School of Dentistry & Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea"},{"name":"Department of Molecular Genetics, School of Dentistry & Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1152\/physrev.00030.2016","article-title":"Dental enamel formation and implications for oral health and disease","volume":"97","author":"Lacruz","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_2","first-page":"684607","article-title":"Dental enamel development: Proteinases and their enamel matrix substrates","volume":"2013","author":"Bartlett","year":"2013","journal-title":"Int. Sch. Res. Not."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Smith, C.E.L., Poulter, J.A., Antanaviciute, A., Kirkham, J., Brookes, S.J., Inglehearn, C.F., and Mighell, A.J. (2017). Amelogenesis Imperfecta; Genes, Proteins, and Pathways. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00435"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1111\/j.1600-0714.1988.tb01332.x","article-title":"Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: Problems in classification","volume":"17","author":"Witkop","year":"1988","journal-title":"J. Oral Pathol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wright, J.T. (2023). Enamel Phenotypes: Genetic and Environmental Determinants. Genes, 14.","DOI":"10.3390\/genes14030545"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1111\/odi.14599","article-title":"Molecular-based phenotype variations in amelogenesis imperfecta","volume":"29","author":"Dong","year":"2023","journal-title":"Oral Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1242\/jcs.108.6.2241","article-title":"Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling","volume":"108","author":"Breuss","year":"1995","journal-title":"J. Cell Sci."},{"key":"ref_8","first-page":"732","article-title":"Critical role for alphavbeta6 integrin in enamel biomineralization","volume":"126","author":"Mohazab","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1093\/hmg\/ddt611","article-title":"ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta","volume":"23","author":"Wang","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/odi.12303","article-title":"Novel ITGB6 mutation in autosomal recessive amelogenesis imperfecta","volume":"21","author":"Seymen","year":"2015","journal-title":"Oral Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1093\/hmg\/ddt616","article-title":"A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta","volume":"23","author":"Poulter","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1038\/ejhg.2015.260","article-title":"Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability","volume":"24","author":"Ansar","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41405-023-00142-y","article-title":"Novel ITGB6 variants cause hypoplastic-hypomineralized amelogenesis imperfecta and taurodontism: Characterization of tooth phenotype and review of literature","volume":"9","author":"Sriwattanapong","year":"2023","journal-title":"BDJ Open"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1177\/0022034518824571","article-title":"WDR72 Mutations Associated with Amelogenesis Imperfecta and Acidosis","volume":"98","author":"Zhang","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kim, Y.J., Gu, S.Y., Chae, W., Kim, S.H., and Kim, J.W. (2024). Critical Considerations in Calling Disease-Causing EDAR Mutations in Nonsyndromic Oligodontia. J. Clin. Med., 13.","DOI":"10.3390\/jcm13237328"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nsmb.1550","article-title":"Nonsense-mediated mRNA decay (NMD) mechanisms","volume":"16","author":"Brogna","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1093\/nar\/gkw010","article-title":"Mechanism and regulation of the nonsense-mediated decay pathway","volume":"44","author":"Hug","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.cell.2016.05.053","article-title":"Leveraging Rules of Nonsense-Mediated mRNA Decay for Genome Engineering and Personalized Medicine","volume":"165","author":"Popp","year":"2016","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100023","DOI":"10.1016\/j.gene.2019.100023","article-title":"The ITGB6 gene: Its role in experimental and clinical biology","volume":"763S","author":"Meecham","year":"2020","journal-title":"Gene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0092-8674(00)80545-0","article-title":"The integrin alpha v beta 6 binds and activates latent TGF beta 1: A mechanism for regulating pulmonary inflammation and fibrosis","volume":"96","author":"Munger","year":"1999","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/nature01413","article-title":"Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema","volume":"422","author":"Morris","year":"2003","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0092-8674(02)00971-6","article-title":"Integrins: Bidirectional, allosteric signaling machines","volume":"110","author":"Hynes","year":"2002","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1002\/ar.20901","article-title":"TGF-beta1 and TGFBR1 are expressed in ameloblasts and promote MMP20 expression","volume":"292","author":"Gao","year":"2009","journal-title":"Anat. Rec."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0014-5793(01)03280-X","article-title":"The integrin alphaVbeta6 binds and activates latent TGFbeta3","volume":"511","author":"Annes","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kim, Y.J., Kang, J., Seymen, F., Koruyucu, M., Gencay, K., Shin, T.J., Hyun, H.K., Lee, Z.H., Hu, J.C., and Simmer, J.P. (2017). Analyses of MMP20 Missense Mutations in Two Families with Hypomaturation Amelogenesis Imperfecta. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00229"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/mgg3.194","article-title":"MMP20, KLK4, and MMP20\/KLK4 double null mice define roles for matrix proteases during dental enamel formation","volume":"4","author":"Hu","year":"2016","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.archoralbio.2004.12.003","article-title":"Variation in dental and skeletal open bite malocclusion in humans with amelogenesis imperfecta","volume":"50","author":"Ravassipour","year":"2005","journal-title":"Arch. Oral Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1080\/00016350802192071","article-title":"Amelogenesis imperfecta-a systematic literature review of associated dental and oro-facial abnormalities and their impact on patients","volume":"66","author":"Poulsen","year":"2008","journal-title":"Acta Odontol. Scand."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/431\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T07:43:27Z","timestamp":1775634207000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["genes17040431"],"URL":"https:\/\/doi.org\/10.3390\/genes17040431","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]}}}