A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis.
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Apr 2022
Apr 2022
Historique:
received:
30
04
2021
accepted:
04
08
2021
pubmed:
20
8
2021
medline:
27
4
2022
entrez:
19
8
2021
Statut:
ppublish
Résumé
In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3'-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.
Identifiants
pubmed: 34410490
doi: 10.1007/s00439-021-02334-8
pii: 10.1007/s00439-021-02334-8
doi:
Substances chimiques
3' Untranslated Regions
0
5' Untranslated Regions
0
Aggrecans
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
951-963Subventions
Organisme : Belgian Federal Science Policy Office
ID : IAP P7/43-BeMGI
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Allin KH, Hansen T, Pedersen OB (2014) The genome and diabetes. Ugeskr Laeger 176(23):2176–2179
Aspberg A (2012) The different roles of aggrecan interaction domains. J Histochem Cytochem 60:987–996. https://doi.org/10.1369/0022155412464376
doi: 10.1369/0022155412464376
pubmed: 23019016
pmcid: 3527881
Bast TH (1933) Development of the otic capsule: II. The origin, development and significance of the fissula ante fenestram and its relation to otosclerotic foci. Arch Otolaryngol 18:1–20. https://doi.org/10.1001/archotol.1933.03580060005001
doi: 10.1001/archotol.1933.03580060005001
Bel Hadj Ali I, Thys M, Beltaief N, Schrauwen I, Hilgert N, Vanderstraeten K, Dieltjens N, Mnif E, Hachicha S, Besbes G, Ben Arab S, Van Camp G (2008) A new locus for otosclerosis, OTSC8, maps to the pericentromeric region of chromosome 9. Hum Genet 123:267–272. https://doi.org/10.1007/s00439-008-0470-3
doi: 10.1007/s00439-008-0470-3
pubmed: 18224337
Boyle EA, O’Roak BJ, Martin BK, Kumar A, Shendure J (2014) MIPgen: optimized modeling and design of molecular inversion probes for targeted resequencing. Bioinformatics (oxford, England) 30:2670–2672. https://doi.org/10.1093/bioinformatics/btu353
doi: 10.1093/bioinformatics/btu353
Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM (2002) Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet 71:618–624. https://doi.org/10.1086/342067
doi: 10.1086/342067
pubmed: 12089654
pmcid: 379196
Brownstein Z, Goldfarb A, Levi H, Frydman M, Avraham KB (2006) Chromosomal mapping and phenotypic characterization of hereditary otosclerosis linked to the OTSC4 locus. Arch Otolaryngol Head Neck Surg 132:416–424. https://doi.org/10.1001/archotol.132.4.416
doi: 10.1001/archotol.132.4.416
pubmed: 16618911
Chapman SC (2011) Can you hear me now? Understanding vertebrate middle ear development. Front Biosci (landmark Edition) 16:1675–1692. https://doi.org/10.2741/3813
doi: 10.2741/3813
pmcid: 3065862
Chen W, Campbell CA, Green GE, Van Den Bogaert K, Komodikis C, Manolidis LS, Aconomou E, Kyamides Y, Christodoulou K, Faghel C, Giguére CM, Alford RL, Manolidis S, Van Camp G, Smith RJH (2002) Linkage of otosclerosis to a third locus (OTSC3) on human chromosome 6p21.3-22.3. J Med Genet 39:473–477. https://doi.org/10.1136/jmg.39.7.473
doi: 10.1136/jmg.39.7.473
pubmed: 12114476
pmcid: 1735167
Chen W, Meyer NC, McKenna MJ, Pfister M, McBride DJ Jr, Fukushima K, Thys M, Camp GV, Smith RJ (2007) Single-nucleotide polymorphisms in the COL1A1 regulatory regions are associated with otosclerosis. Clin Genet 71:406–414. https://doi.org/10.1111/j.1399-0004.2007.00794.x
doi: 10.1111/j.1399-0004.2007.00794.x
pubmed: 17489845
Clark K, Sowers MR, Wallace RB, Jannausch ML, Lemke J, Anderson CV (1995) Age-related hearing loss and bone mass in a population of rural women aged 60 to 85 years. Ann Epidemiol 5:8–14
doi: 10.1016/1047-2797(94)00035-R
Consortium UK, Walter K, Min JL, Huang J, Crooks L, Memari Y, McCarthy S, Perry JRB, Xu C, Futema M, Lawson D, Iotchkova V, Schiffels S, Hendricks AE, Danecek P, Li R, Floyd J, Wain LV, Barroso I, Humphries SE, Hurles ME, Zeggini E, Barrett JC, Plagnol V, Richards JB, Greenwood CMT, Timpson NJ, Durbin R, Soranzo N (2015) The UK10K project identifies rare variants in health and disease. Nature 526:82–90. https://doi.org/10.1038/nature14962
doi: 10.1038/nature14962
Dawson SJ, Crompton M, Ziff J, Mowat A, Lavy JA, Saeed SR (2018) Progress in identifying genes underlying familial Otosclerosis using a Whole Exome sequencing approach. Mol Biol Hear Deafness (abstract)
Declau F, Van Spaendonck M, Timmermans JP, Michaels L, Liang J, Qiu JP, Van de Heyning P (2001) Prevalence of otosclerosis in an unselected series of temporal bones. Otol Neurotol 22:596–602
doi: 10.1097/00129492-200109000-00006
Ficker M, Powles N, Warr N, Pirvola U, Maconochie M (2004) Analysis of genes from inner ear developmental-stage cDNA subtraction reveals molecular regionalization of the otic capsule. Dev Biol 268:7–23. https://doi.org/10.1016/j.ydbio.2003.11.023
doi: 10.1016/j.ydbio.2003.11.023
pubmed: 15031101
Fukuhara Y, Cho SY, Miyazaki O, Hattori A, Seo J-H, Mashima R, Kosuga M, Fukami M, Jin D-K, Okuyama T, Nishimura G (2019) The second report on spondyloepimetaphyseal dysplasia, aggrecan type: a milder phenotype than originally reported. Clin Dysmorphol 28:26–29. https://doi.org/10.1097/MCD.0000000000000241
doi: 10.1097/MCD.0000000000000241
pubmed: 30124491
Gordon MA (1989) The genetics of otosclerosis: a review. Am J Otol 10:426–438
pubmed: 2692453
Hiatt JB, Pritchard CC, Salipante SJ, O’Roak BJ, Shendure J (2013) Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation. Genome Res 23:843–854. https://doi.org/10.1101/gr.147686.112
doi: 10.1101/gr.147686.112
pubmed: 23382536
pmcid: 3638140
Hindorff LA, Gillanders EM, Manolio TA (2011) Genetic architecture of cancer and other complex diseases: lessons learned and future directions. Carcinogenesis 32:945–954. https://doi.org/10.1093/carcin/bgr056
doi: 10.1093/carcin/bgr056
pubmed: 21459759
pmcid: 3140138
Hoffmann TJ, Keats BJ, Yoshikawa N, Schaefer C, Risch N, Lustig LR (2016) A large genome-wide association study of age-related hearing impairment using electronic health records. PLoS Genet 12:e1006371. https://doi.org/10.1371/journal.pgen.1006371
doi: 10.1371/journal.pgen.1006371
pubmed: 27764096
pmcid: 5072625
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O’Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME, Neale BM, Daly MJ, MacArthur DG (2019) Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. bioRxiv. https://doi.org/10.1101/531210
doi: 10.1101/531210
Khalfallah A, Schrauwen I, Mnejja M, HadjKacem H, Dhouib L, Mosrati MA, Hakim B, Lahmar I, Charfeddine I, Driss N, Ayadi H, Ghorbel A, Van Camp G, Masmoudi S (2011) Association of COL1A1 and TGFB1 polymorphisms with otosclerosis in a Tunisian population. Ann Hum Genet 75:598–604. https://doi.org/10.1111/j.1469-1809.2011.00665.x
doi: 10.1111/j.1469-1809.2011.00665.x
pubmed: 21777208
Kiani C, Chen L, Wu YJ, Yee AJ, Yang BB (2002) Structure and function of aggrecan. Cell Res 12:19–32. https://doi.org/10.1038/sj.cr.7290106
doi: 10.1038/sj.cr.7290106
pubmed: 11942407
Lauing KL, Cortes M, Domowicz MS, Henry JG, Baria AT, Schwartz NB (2014) Aggrecan is required for growth plate cytoarchitecture and differentiation. Dev Biol 396:224–236. https://doi.org/10.1016/j.ydbio.2014.10.005
doi: 10.1016/j.ydbio.2014.10.005
pubmed: 25446537
pmcid: 4261049
Mangino M, Flex E, Capon F, Sangiuolo F, Carraro E, Gualandi F, Mazzoli M, Martini A, Novelli G, Dallapiccola B (2001) Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26. Eur J Hum Genet 9:667–671. https://doi.org/10.1038/sj.ejhg.5200707
doi: 10.1038/sj.ejhg.5200707
pubmed: 11571554
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TFC, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461:747–753. https://doi.org/10.1038/nature08494
doi: 10.1038/nature08494
pubmed: 19812666
pmcid: 2831613
Mariella E, Marotta F, Grassi E, Gilotto S, Provero P (2019) The length of the expressed 3′ UTR is an intermediate molecular phenotype linking genetic variants to complex diseases. Front Genet 10:714–714. https://doi.org/10.3389/fgene.2019.00714
doi: 10.3389/fgene.2019.00714
pubmed: 31475030
pmcid: 6707137
McKenna MJ, Kristiansen AG, Bartley ML, Rogus JJ, Haines JL (1998) Association of COL1A1 and otosclerosis: evidence for a shared genetic etiology with mild osteogenesis imperfecta. Am J Otol 19:604–610
pubmed: 9752968
Milroy CM, Michaels L (1990) Pathology of the otic capsule. J Laryngol Otol 104:83–90. https://doi.org/10.1017/s0022215100111946
doi: 10.1017/s0022215100111946
pubmed: 2324629
Moumoulidis I, Axon P, Baguley D, Reid E (2007) A review on the genetics of otosclerosis. Clin Otolaryngol 32:239–247. https://doi.org/10.1111/j.1365-2273.2007.01475.x
doi: 10.1111/j.1365-2273.2007.01475.x
pubmed: 17651264
Nilsson O, Guo MH, Dunbar N, Popovic J, Flynn D, Jacobsen C, Lui JC, Hirschhorn JN, Baron J, Dauber A (2014) Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J Clin Endocrinol Metab 99:E1510–E1518. https://doi.org/10.1210/jc.2014-1332
doi: 10.1210/jc.2014-1332
pubmed: 24762113
pmcid: 4121031
O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O’Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J (2012) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science (new York, N.y.) 338:1619–1622. https://doi.org/10.1126/science.1227764
doi: 10.1126/science.1227764
Ovadia M, Parker CH, Lash JW (1980) Changing patterns of proteoglycan synthesis during chondrogenic differentiation. J Embryol Exp Morphol 56:59–70
pubmed: 7400751
Priyadarshi S, Ray CS, Biswal NC, Nayak SR, Panda KC, Desai A, Ramchander PV (2015) Genetic association and altered gene expression of osteoprotegerin in otosclerosis patients. Ann Hum Genet 79:225–237. https://doi.org/10.1111/ahg.12118
doi: 10.1111/ahg.12118
pubmed: 25998045
Quesnel AM, Ishai R, McKenna MJ (2018) Otosclerosis: temporal bone pathology. Otolaryngol Clin N Am 51:291–303. https://doi.org/10.1016/j.otc.2017.11.001
doi: 10.1016/j.otc.2017.11.001
Rämö JT, Kiiskinen T, Karjalainen J, Krebs K, Kurki M, Havulinna AS, Hämäläinen E, Häppölä P, Hautakangas H, Karczewski KJ, Kanai M, Mägi R, Palta P, Esko T, Metspalu A, Pirinen M, Ripatti S, Milani L, Mäkitie A, Daly MJ, Palotie A (2020) Genome-wide screen of otosclerosis in population biobanks: 18 loci and shared heritability with skeletal structure. medRxiv. https://doi.org/10.1101/2020.11.15.20227868
doi: 10.1101/2020.11.15.20227868
Ruoslahti E, Yamaguchi Y (1991) Proteoglycans as modulators of growth factor activities. Cell 64:867–869. https://doi.org/10.1016/0092-8674(91)90308-l
doi: 10.1016/0092-8674(91)90308-l
pubmed: 2001586
San Lucas FA, Wang G, Scheet P, Peng B (2012) Integrated annotation and analysis of genetic variants from next-generation sequencing studies with variant tools. Bioinformatics 28:421–422. https://doi.org/10.1093/bioinformatics/btr667
doi: 10.1093/bioinformatics/btr667
pubmed: 22138362
Schrauwen I, Thys M, Vanderstraeten K, Fransen E, Dieltjens N, Huyghe JR, Ealy M, Claustres M, Cremers CRWJ, Dhooge I, Declau F, Van de Heyning P, Vincent R, Somers T, Offeciers E, Smith RJH, Van Camp G (2008) Association of bone morphogenetic proteins with otosclerosis. J Bone Min Res 23:507–516. https://doi.org/10.1359/jbmr.071112
doi: 10.1359/jbmr.071112
Schrauwen I, Ealy M, Huentelman MJ, Thys M, Homer N, Vanderstraeten K, Fransen E, Corneveaux JJ, Craig DW, Claustres M, Cremers CWRJ, Dhooge I, Van de Heyning P, Vincent R, Offeciers E, Smith RJH, Van Camp G (2009) A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis. Am J Hum Genet 84:328–338. https://doi.org/10.1016/j.ajhg.2009.01.023
doi: 10.1016/j.ajhg.2009.01.023
pubmed: 19230858
pmcid: 2667982
Schrauwen I, Weegerink NJ, Fransen E, Claes C, Pennings RJ, Cremers CW, Huygen PL, Kunst HP, Van Camp G (2011) A new locus for otosclerosis, OTSC10, maps to chromosome 1q41-44. Clin Genet 79:495–497. https://doi.org/10.1111/j.1399-0004.2010.01576.x
doi: 10.1111/j.1399-0004.2010.01576.x
pubmed: 21470211
Schrauwen I, Khalfallah A, Ealy M, Fransen E, Claes C, Huber A, Murillo LR, Masmoudi S, Smith RJ, Van Camp G (2012) COL1A1 association and otosclerosis: a meta-analysis. Am J Med Genet A 158a:1066–1070. https://doi.org/10.1002/ajmg.a.35276
doi: 10.1002/ajmg.a.35276
pubmed: 22489040
Schrauwen I, Valgaeren H, Tomas-Roca L, Sommen M, Altunoglu U, Wesdorp M, Beyens M, Fransen E, Nasir A, Vandeweyer G, Schepers A, Rahmoun M, van Beusekom E, Huentelman MJ, Offeciers E, Dhooghe I, Huber A, Van de Heyning P, Zanetti D, De Leenheer EMR, Gilissen C, Hoischen A, Cremers CW, Verbist B, de Brouwer APM, Padberg GW, Pennings R, Kayserili H, Kremer H, Van Camp G, van Bokhoven H (2019) Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis. Genet Med 21:1199–1208. https://doi.org/10.1038/s41436-018-0300-5
doi: 10.1038/s41436-018-0300-5
pubmed: 30287925
Sommen M, Van Camp G, Liktor B, Csomor P, Fransen E, Sziklai I, Schrauwen I, Karosi T (2014) Genetic association analysis in a clinically and histologically confirmed otosclerosis population confirms association with the TGFB1 gene but suggests an association of the RELN gene with a clinically indistinguishable otosclerosis-like phenotype. Otol Neurotol 35:1058–1064. https://doi.org/10.1097/mao.0000000000000334
doi: 10.1097/mao.0000000000000334
pubmed: 24643032
Stattin E-L, Wiklund F, Lindblom K, Onnerfjord P, Jonsson B-A, Tegner Y, Sasaki T, Struglics A, Lohmander S, Dahl N, Heinegård D, Aspberg A (2010) A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans. Am J Hum Genet 86:126–137. https://doi.org/10.1016/j.ajhg.2009.12.018
doi: 10.1016/j.ajhg.2009.12.018
pubmed: 20137779
pmcid: 2820178
Stavber L, Hovnik T, Kotnik P, Lovrecic L, Kovac J, Tesovnik T, Bertok S, Dovc K, Debeljak M, Battelino T, Avbelj Stefanija M (2020) High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature. Eur J Endocrinol 182:243–253. https://doi.org/10.1530/eje-19-0771
doi: 10.1530/eje-19-0771
pubmed: 31841439
Sykes B, Ogilvie D, Wordsworth P, Anderson JN (1986) Osteogenesis imperfecta is linked to both type I collagen structural genes. Lancet 2:69–72
doi: 10.1016/S0140-6736(86)91609-0
Sykes B, Ogilvie D, Wordsworth P, Wallis G, Mathew C, Beighton P, Nicholls A, Pope FM, Thompson E, Tsipouras P et al (1990) Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2. Am J Hum Genet 46:293–307
pubmed: 1967900
pmcid: 1684971
The Genomes Project C (2015) A global reference for human genetic variation. Nature 526: 68. https://doi.org/10.1038/nature15393 . https://www.nature.com/articles/nature15393#supplementary-information
Thorisson GA, Smith AV, Krishnan L, Stein LD (2005) The International HapMap Project Web site. Genome Res 15:1592–1593. https://doi.org/10.1101/gr.4413105
doi: 10.1101/gr.4413105
pubmed: 16251469
pmcid: 1310647
Thys M, Schrauwen I, Vanderstraeten K, Janssens K, Dieltjens N, Van Den Bogaert K, Fransen E, Chen W, Ealy M, Claustres M, Cremers CR, Dhooge I, Declau F, Claes J, Van de Heyning P, Vincent R, Somers T, Offeciers E, Smith RJ, Van Camp G (2007a) The coding polymorphism T263I in TGF-beta1 is associated with otosclerosis in two independent populations. Hum Mol Genet 16:2021–2030. https://doi.org/10.1093/hmg/ddm150
doi: 10.1093/hmg/ddm150
pubmed: 17588962
Thys M, Van Den Bogaert K, Iliadou V, Vanderstraeten K, Dieltjens N, Schrauwen I, Chen W, Eleftheriades N, Grigoriadou M, Pauw RJ, Cremers CRWJ, Smith RJH, Petersen MB, Van Camp G (2007b) A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13–16.1. Eur J Hum Genet 15:362–368. https://doi.org/10.1038/sj.ejhg.5201761
doi: 10.1038/sj.ejhg.5201761
pubmed: 17213839
Tomek MS, Brown MR, Mani SR, Ramesh A, Srisailapathy CR, Coucke P, Zbar RI, Bell AM, McGuirt WT, Fukushima K, Willems PJ, Van Camp G, Smith RJ (1998) Localization of a gene for otosclerosis to chromosome 15q25-q26. Hum Mol Genet 7:285–290. https://doi.org/10.1093/hmg/7.2.285
doi: 10.1093/hmg/7.2.285
pubmed: 9425236
Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, Rozen SG (2012) Primer3–new capabilities and interfaces. Nucleic Acids Res 40:e115–e115. https://doi.org/10.1093/nar/gks596
doi: 10.1093/nar/gks596
pubmed: 22730293
pmcid: 3424584
Valgaeren H, Sommen M, Beyens M, Vandeweyer G, Schrauwen I, Schepers A, Schatteman I, Topsakal V, Dhooge I, Kunst H, Zanetti D, Huber AM, Hoischen A, Fransen E, Van Camp G (2019) Insufficient evidence for a role of SERPINF1 in otosclerosis. Mol Genet Genomics 294:1001–1006. https://doi.org/10.1007/s00438-019-01558-8
doi: 10.1007/s00438-019-01558-8
pubmed: 30968248
Valhmu WB, Palmer GD, Dobson J, Fischer SG, Ratcliffe A (1998) Regulatory activities of the 5′- and 3′-untranslated regions and promoter of the human aggrecan gene. J Biol Chem 273:6196–6202. https://doi.org/10.1074/jbc.273.11.6196
doi: 10.1074/jbc.273.11.6196
pubmed: 9497342
Van Den Bogaert K, Govaerts PJ, Schatteman I, Brown MR, Caethoven G, Offeciers FE, Somers T, Declau F, Coucke P, Van de Heyning P, Smith RJ, Van Camp G (2001) A second gene for otosclerosis, OTSC2, maps to chromosome 7q34-36. Am J Hum Genet 68:495–500. https://doi.org/10.1086/318185
doi: 10.1086/318185
Van Den Bogaert K, De Leenheer EMR, Chen W, Lee Y, Nürnberg P, Pennings RJE, Vanderstraeten K, Thys M, Cremers CWRJ, Smith RJH, Van Camp G (2004) A fifth locus for otosclerosis, OTSC5, maps to chromosome 3q22-24. J Med Genet 41:450–453. https://doi.org/10.1136/jmg.2004.018671
doi: 10.1136/jmg.2004.018671
Watanabe H, Kimata K, Line S, Strong D, Gao LY, Kozak CA, Yamada Y (1994) Mouse cartilage matrix deficiency (cmd) caused by a 7 bp deletion in the aggrecan gene. Nat Genet 7:154–157. https://doi.org/10.1038/ng0694-154
doi: 10.1038/ng0694-154
pubmed: 7920633
Yoo TJ, Cho H, Yamada Y (1991) Hearing impairment in mice with the cmd/cmd (cartilage matrix deficiency) mutant gene. Ann NY Acad Sci 630:265–267. https://doi.org/10.1111/j.1749-6632.1991.tb19600.x
doi: 10.1111/j.1749-6632.1991.tb19600.x
pubmed: 1952601
Ziff JL, Crompton M, Powell HR, Lavy JA, Aldren CP, Steel KP, Saeed SR, Dawson SJ (2016) Mutations and altered expression of SERPINF1 in patients with familial otosclerosis. Hum Mol Genet 25:2393–2403. https://doi.org/10.1093/hmg/ddw106
doi: 10.1093/hmg/ddw106
pubmed: 27056980
pmcid: 5181625