{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T09:48:52Z","timestamp":1788515332901,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T00:00:00Z","timestamp":1655510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The Stickler syndromes are a group of genetic connective tissue disorders associated with an increased risk of rhegmatogenous retinal detachment, deafness, cleft palate, and premature arthritis. This review article focuses on the molecular genetics of the autosomal dominant forms of the disease. Pathogenic variants in COL2A1 causing Stickler syndrome usually result in haploinsufficiency of the protein, whereas pathogenic variants of type XI collagen more usually exert dominant negative effects. The severity of the disease phenotype is thus dependent on the location and nature of the mutation, as well as the normal developmental role of the respective protein.<\/jats:p>","DOI":"10.3390\/genes13061089","type":"journal-article","created":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T09:51:11Z","timestamp":1655545871000},"page":"1089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Dominant Stickler Syndrome"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4226-6005","authenticated-orcid":false,"given":"Zack","family":"Soh","sequence":"first","affiliation":[{"name":"John van Geest Centre for Brain Repair, Vitreoretinal Research Group, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan J.","family":"Richards","sequence":"additional","affiliation":[{"name":"John van Geest Centre for Brain Repair, Vitreoretinal Research Group, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK"},{"name":"NHS England Highly Specialised Stickler Syndrome Diagnostic Service, Cambridge University, NHS Foundation Trust, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"McNinch","sequence":"additional","affiliation":[{"name":"John van Geest Centre for Brain Repair, Vitreoretinal Research Group, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK"},{"name":"NHS England Highly Specialised Stickler Syndrome Diagnostic Service, Cambridge University, NHS Foundation Trust, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2399-4154","authenticated-orcid":false,"given":"Philip","family":"Alexander","sequence":"additional","affiliation":[{"name":"NHS England Highly Specialised Stickler Syndrome Diagnostic Service, Cambridge University, NHS Foundation Trust, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1618-7557","authenticated-orcid":false,"given":"Howard","family":"Martin","sequence":"additional","affiliation":[{"name":"John van Geest Centre for Brain Repair, Vitreoretinal Research Group, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK"},{"name":"NHS England Highly Specialised Stickler Syndrome Diagnostic Service, Cambridge University, NHS Foundation Trust, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0042-8659","authenticated-orcid":false,"given":"Martin P.","family":"Snead","sequence":"additional","affiliation":[{"name":"John van Geest Centre for Brain Repair, Vitreoretinal Research Group, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK"},{"name":"NHS England Highly Specialised Stickler Syndrome Diagnostic Service, Cambridge University, NHS Foundation Trust, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"ref_1","unstructured":"Robin, N.H., Moran, R.T., and Ala-Kokko, L. (2021). Stickler Syndrome. GeneReviews(\u00ae), University of Washington."},{"key":"ref_2","first-page":"2633004020978661","article-title":"Therapeutic and diagnostic advances in Stickler syndrome","volume":"1","author":"Snead","year":"2020","journal-title":"Ther. Adv. Rare Disease"},{"key":"ref_3","first-page":"433","article-title":"Hereditary Progressive Arthro-Ophthalmopathy","volume":"40","author":"Stickler","year":"1965","journal-title":"Mayo Clin. Proc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/0888-7543(87)90027-9","article-title":"The Stickler syndrome: Evidence for close linkage to the structural gene for type II collagen","volume":"1","author":"Francomano","year":"1987","journal-title":"Genomics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6624","DOI":"10.1073\/pnas.88.15.6624","article-title":"Stop codon in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy)","volume":"88","author":"Ahmad","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/(SICI)1096-8628(19960614)63:3<461::AID-AJMG9>3.0.CO;2-U","article-title":"A-2-->G transition at the 3\u2019 acceptor splice site of IVS17 characterizes the COL2A1 gene mutation in the original Stickler syndrome kindred","volume":"63","author":"Williams","year":"1996","journal-title":"Am J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/eye.1994.153","article-title":"Stickler syndrome: Correlation between vitreoretinal phenotypes and linkage to COL 2A1","volume":"8","author":"Snead","year":"1994","journal-title":"Eye"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1093\/hmg\/5.9.1339","article-title":"A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen","volume":"5","author":"Richards","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/j.1749-6632.1996.tb56300.x","article-title":"Stickler syndrome type 2 and linkage to the COL11A1 gene","volume":"785","author":"Snead","year":"1996","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1093\/hmg\/3.9.1561","article-title":"A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene","volume":"3","author":"Brunner","year":"1994","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/S0022-3476(98)70466-4","article-title":"Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha2(XI) chain of type XI collagen","volume":"132","author":"Murray","year":"1998","journal-title":"J. Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1038\/eye.2011.201","article-title":"Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist","volume":"25","author":"Snead","year":"2011","journal-title":"Eye"},{"key":"ref_13","first-page":"1","article-title":"Stickler syndrome-lessons from a national cohort","volume":"5","author":"Snead","year":"2021","journal-title":"Eye"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.preteyeres.2004.04.002","article-title":"Collagens and collagen-related matrix components in the human and mouse eye","volume":"23","author":"Pelliniemi","year":"2004","journal-title":"Prog; Retin. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jmg.2009.072785","article-title":"The revised Ghent nosology for the Marfan syndrome","volume":"47","author":"Loeys","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_16","unstructured":"Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). Loeys-Dietz Syndrome. GeneReviews(\u00ae), University of Washington."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/978-94-007-7893-1_7","article-title":"Loeys-Dietz syndrome","volume":"802","author":"Dietz","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_18","unstructured":"Kloeckener-Gruissem, B., and Amstutz, C. (2016). VCAN-Related Vitreoretinopathy. GeneReviews(\u00ae), University of Washington."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1136\/bjo.2006.104406","article-title":"Clinical characterisation and molecular analysis of Wagner syndrome","volume":"91","author":"Meredith","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1038\/sj.ejhg.5201913","article-title":"Czech dysplasia metatarsal type: Another type II collagen disorder","volume":"15","author":"Hoornaert","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, S., Wang, Y., Sun, L., Yan, W., Huang, L., Zhang, Z., Zhang, T., and Ding, X. (2021). Knobloch Syndrome Associated with Novel COL18A1 Variants in Chinese Population. Genes, 12.","DOI":"10.3390\/genes12101512"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1167\/iovs.04-1017","article-title":"A novel mutation of COL2A1 resulting in dominantly inherited rhegmatogenous retinal detachment","volume":"46","author":"Richards","year":"2005","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1002\/humu.23050","article-title":"Deep Intronic Sequence Variants in COL2A1 Affect the Alternative Splicing Efficiency of Exon 2, and May Confer a Risk for Rhegmatogenous Retinal Detachment","volume":"37","author":"Spickett","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/ANC.0000000000000766","article-title":"A Case Report of Donnai-Barrow Syndrome","volume":"21","author":"Robinson","year":"2021","journal-title":"Adv. Neonatal. Care"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1038\/ng2063","article-title":"Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes","volume":"39","author":"Kantarci","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1097\/01.JAA.0000657160.48246.91","article-title":"A review of Ehlers-Danlos syndrome","volume":"33","author":"Miller","year":"2020","journal-title":"Jaapa"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E1461","DOI":"10.1002\/humu.21257","article-title":"Stickler syndrome and the vitreous phenotype: Mutations in COL2A1 and COL11A1","volume":"31","author":"Richards","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.1046\/j.1432-1033.2003.03711.x","article-title":"Assembly of collagen types II, IX and XI into nascent hetero-fibrils by a rat chondrocyte cell line","volume":"270","author":"Fernandes","year":"2003","journal-title":"Eur. J. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/humu.20347","article-title":"High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: Vitreoretinal assessment coupled with exon sequencing for screening COL2A1","volume":"27","author":"Richards","year":"2006","journal-title":"Hum. Mutat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/humu.9497","article-title":"Missense and silent mutations in COL2A1 result in Stickler syndrome but via different molecular mechanisms","volume":"28","author":"Richards","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/eye.2008.34","article-title":"The influence of pre-mRNA splicing on phenotypic modification in Stickler\u2019s syndrome and other type II collagenopathies","volume":"22","author":"Richards","year":"2008","journal-title":"Eye"},{"key":"ref_32","first-page":"1083","article-title":"Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix","volume":"67","author":"Richards","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1097\/MAO.0b013e3181c0e621","article-title":"Collagen type distribution in the healthy human tympanic membrane","volume":"30","author":"Knutsson","year":"2009","journal-title":"Otol. Neurotol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1136\/jmg.12.4.397","article-title":"The Stickler syndrome presenting as a dominantly inherited cleft palate and blindness","volume":"12","author":"Hall","year":"1975","journal-title":"J. Med. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.otc.2016.05.003","article-title":"Eustachian Tube Function","volume":"49","author":"Ars","year":"2016","journal-title":"Otolaryngol. Clin. N. Am."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1136\/bjo.84.4.364","article-title":"COL2A1 exon 2 mutations: Relevance to the Stickler and Wagner syndromes","volume":"84","author":"Richards","year":"2000","journal-title":"Br. J. Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.ymgme.2014.09.001","article-title":"Novel pathogenic COL11A1\/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing","volume":"113","author":"Acke","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1136\/jmedgenet-2012-101499","article-title":"Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss","volume":"50","author":"Richards","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Luo, Y., and Karsdal, M. (2016). Type XI Collagen. Biochemistry of Collagens, Laminins and Elastin, Academic Press.","DOI":"10.1016\/B978-0-12-809847-9.00011-8"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1750-1172-7-84","article-title":"Hearing impairment in Stickler syndrome: A systematic review","volume":"7","author":"Acke","year":"2012","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1080\/00016480410016162","article-title":"Col11a1 and Col11a2 mRNA expression in the developing mouse cochlea: Implications for the correlation of hearing loss phenotype with mutant type XI collagen genotype","volume":"124","author":"Shpargel","year":"2004","journal-title":"Acta Otolaryngol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1007\/s00405-020-06306-y","article-title":"Auditory dysfunction in type 2 Stickler Syndrome","volume":"278","author":"Alexander","year":"2021","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"111s","DOI":"10.1177\/0003489415575044","article-title":"Non-ocular Stickler syndrome with a novel mutation in COL11A2 diagnosed by massively parallel sequencing in Japanese hearing loss patients","volume":"124","author":"Iwasa","year":"2015","journal-title":"Ann. Otol. Rhinol Laryngol"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/ajmg.a.30111","article-title":"A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome","volume":"130","author":"Vuoristo","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20170335","DOI":"10.1098\/rstb.2017.0335","article-title":"The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis","volume":"373","author":"Lawrence","year":"2018","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41431-018-0316-y","article-title":"Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia","volume":"27","author":"Nixon","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s00439-011-0968-y","article-title":"BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome","volume":"130","author":"Reis","year":"2011","journal-title":"Hum. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Behesti, H., Holt, J.K., and Sowden, J.C. (2006). The level of BMP4 signaling is critical for the regulation of distinct T-box gene expression domains and growth along the dorso-ventral axis of the optic cup. BMC Dev. Biol., 6.","DOI":"10.1186\/1471-213X-6-62"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1007\/s00467-009-1287-6","article-title":"Functional analysis of BMP4 mutations identified in pediatric CAKUT patients","volume":"24","author":"Tabatabaeifar","year":"2009","journal-title":"Pediatr. Nephrol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/6\/1089\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:34:48Z","timestamp":1760139288000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/6\/1089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,18]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["genes13061089"],"URL":"https:\/\/doi.org\/10.3390\/genes13061089","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,18]]}}}