Targeted next‑generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment

Huang,Xinhua; Lin,Ying; Chen,Chuan; Zhu,Yi; Gao,Hongbin; Li,Tao; Liu,Bingqian; Lyu,Cancan; Huang,Ying; Wu,Qingxiu; Li,Haichun; Jin,Chenjin; Liang,Xiaoling; Lu,Lin

doi:10.3892/ijmm.2018.3752

Targeted next‑generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment

Authors:
- Xinhua Huang
- Ying Lin
- Chuan Chen
- Yi Zhu
- Hongbin Gao
- Tao Li
- Bingqian Liu
- Cancan Lyu
- Ying Huang
- Qingxiu Wu
- Haichun Li
- Chenjin Jin
- Xiaoling Liang
- Lin Lu
View Affiliations

Affiliations: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China, Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: July 4, 2018 https://doi.org/10.3892/ijmm.2018.3752
Pages: 1819-1826
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Stickler syndrome is a group of inherited connective tissue disorders characterized by distinctive facial and ocular abnormalities, hearing loss and early‑onset arthritis. The aim of the present study was to investigate the genetic changes in two Chinese patients with Stickler syndrome, manifested as bilateral retinal detachment and peripheral retinal degeneration. Complete ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination and fundus examination, were performed. Genomic DNA was extracted from leukocytes of the peripheral blood collected from the patients, their unaffected family members and 200 unrelated control subjects from the same population. Next‑generation sequencing of established genes associated with ocular disease was performed. A heterozygous collagen type II α1 chain (COL2A1) mutation c.1310G>C (p.R437P) in exon 21 was identified in Family 1 and a heterozygous COL2A1 mutation c.2302‑1G>A in intron 34 was identified in Family 2. The functional effects of the mutations were assessed by polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT) analysis. The c.1310G>C mutation was predicted to damage protein structure and function, and the c.2302‑1G>A mutation was predicted to result in a splicing defect. The findings of the current study expand the established mutation spectrum of COL2A1, and may facilitate genetic counseling and development of therapeutic strategies for patients with Stickler syndrome.

View Figures

View References

1	Stickler GB, Belau PG, Farrell FJ, Joes JD, Pugh DG, Steinberg AG and Ward LE: Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc. 40:433–455. 1965.PubMed/NCBI
2	Robin NH, Moran RT and Ala-Kokko L: Stickler syndrome. GeneReviews^®. Adam MP, Ardinger HH, Pagon RA, et al: Seattle, WA: 1993
3	Rishi P, Maheshwari A and Rishi E: Stickler syndrome. Indian J Ophthalmol. 63:614–615. 2015. View Article : Google Scholar : PubMed/NCBI
4	Bennett JT and McMurray SW: Stickler syndrome. J Pediatr Orthop. 10:760–763. 1990. View Article : Google Scholar : PubMed/NCBI
5	Aylward B, daCruz L, Ezra E, Sullivan P, MacLaren RE, Charteris D, Gregor Z, Bainbridge J and Minihan M: Stickler syndrome. Ophthalmology. 115:1636–1637. 2008. View Article : Google Scholar : PubMed/NCBI
6	Snead MP, McNinch AM, Poulson AV, Bearcroft P, Silverman B, Gomersall P, Parfect V and Richards AJ: Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (Lond). 25:1389–1400. 2011. View Article : Google Scholar
7	Savasta S, Salpietro V, Spartà MV, Foiadelli T, Laino D, Lobefalo L, Marseglia GL and Verrotti A: Stickler syndrome associated with epilepsy: Report of three cases. Eur J Pediatr. 174:697–701. 2015. View Article : Google Scholar : PubMed/NCBI
8	Goyal M, Kapoor S, Ikegawa S and Nishimura G: Stickler syndrome type 1 with short stature and atypical ocular manifestations. Case Rep Pediatr. 2016:31985972016.PubMed/NCBI
9	Faber J, Winterpacht A, Zabel B, Gnoinski W, Schinzel A, Steinmann B and Superti-Furga A: Clinical variability of Stickler syndrome with a COL2A1 haploinsufficiency mutation: Implications for genetic counselling. J Med Genet. 37:318–320. 2000. View Article : Google Scholar : PubMed/NCBI
10	Ang A, Ung T, Puvanachandra N, Wilson L, Howard F, Ryalls M, Richards A, Meredith S, Laidlaw M, Poulson A, et al: Vitreous phenotype: A key diagnostic sign in Stickler syndrome types 1 and 2 complicated by double heterozygosity. Am J Med Genet A. 143A:604–607. 2007. View Article : Google Scholar : PubMed/NCBI
11	Alexander P, Poulson A, McNinch A, Richards A and Snead M: Type I membranous anomaly in Stickler syndrome. Ophthalmic Genet. 39:1472018. View Article : Google Scholar
12	Leung L, Hyland JC, Young A, Goldberg MF and Handa JT: A novel mutation in intron 11 of the COL2A1 gene in a patient with type 1 Stickler syndrome. Retina. 26:106–109. 2006. View Article : Google Scholar : PubMed/NCBI
13	Richards AJ, Yates JR, Williams R, Payne SJ, Pope FM, Scott JD and Snead MP: A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in a1 (XI) collagen. Hum Mol Genet. 5:1339–1343. 1996. View Article : Google Scholar : PubMed/NCBI
14	Brunner HG, van Beersum SE, Warman ML, Olsen BR, Ropers HH and Mariman EC: A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. Hum Mol Genet. 3:1561–1564. 1994. View Article : Google Scholar : PubMed/NCBI
15	Giedion A, Brandner M, Lecannellier J, Muhar U, Prader A, Sulzer J and Zweymüller E: Oto-spondylo-megaepiphyseal dysplasia (OSMED). Helv Paediatr Acta. 37:361–380. 1982.PubMed/NCBI
16	Van Camp G, Snoeckx RL, Hilgert N, van den Ende J, Fukuoka H, Wagatsuma M, Suzuki H, Smets RM, Vanhoenacker F, Declau F, et al: A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am J Hum Genet. 79:449–457. 2006. View Article : Google Scholar : PubMed/NCBI
17	Rose PS, Levy HP, Liberfarb RM, Davis J, Szymko-Bennett Y, Rubin BI, Tsilou E, Griffith AJ and Francomano CA: Stickler syndrome: Clinical characteristics and diagnostic criteria. Am J Med Genet A. 138A:199–207. 2005. View Article : Google Scholar : PubMed/NCBI
18	Barat-Houari M, Sarrabay G, Gatinois V, Fabre A, Dumont B, Genevieve D and Touitou I: Mutation update for COL2A1 gene variants associated with type II collagenopathies. Hum Mutat. 37:7–15. 2016. View Article : Google Scholar
19	Scott JE: The chemical morphology of the vitreous. Eye (Lond). 6:553–555. 1992. View Article : Google Scholar
20	Richards AJ, Baguley DM, Yates JR, Lane C, Nicol M, Harper PS, Scott JD and Snead MP: 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. Am J Hum Genet. 67:1083–1094. 2000.PubMed/NCBI
21	Prockop DJ and Kivirikko KI: Collagens: Molecular biology, diseases, and potentials for therapy. Annu Rev Biochem. 64:403–434. 1995. View Article : Google Scholar : PubMed/NCBI
22	Lin Y, Gao H, Chen C, Zhu Y, Li T, Liu B, Ma C, Jiang H, Li Y, Huang Y, et al: Clinical and next-generation sequencing findings in a Chinese family exhibiting severe familial exudative vitreoretinopathy. Int J Mol Med. 41:773–782. 2018.
23	Li T, Lin Y, Gao H, Chen C, Zhu Y, Liu B, Lian Y, Li Y, Zhou W, Jiang H, et al: Two heterozygous mutations identified in one Chinese patient with bilateral macular coloboma. Mol Med Rep. 16:2505–2510. 2017. View Article : Google Scholar : PubMed/NCBI
24	Lin Y, Liang X, Ai S, Chen C, Liu X, Luo L, Ye S, Li B, Liu Y and Yang H: FGFR2 molecular analysis and related clinical findings in one Chinese family with Crouzon syndrome. Mol Vis. 18:449–454. 2012.PubMed/NCBI
25	Lin Y, Liu X, Yu S, Luo L, Liang X, Wang Z, Chen C, Zhu Y, Ye S, Yan H and Liu Y: PAX6 analysis of two sporadic patients from southern China with classic aniridia. Mol Vis. 18:2190–2194. 2012.PubMed/NCBI
26	Lin Y, Gao H, Ai S, Eswarakumar JVP, Chen C, Zhu Y, Li T, Liu B, Liu X, Luo L, et al: C278F mutation in FGFR2 gene causes two different types of syndromic craniosynostosis in two Chinese patients. Mol Med Rep. 16:5333–5337. 2017. View Article : Google Scholar : PubMed/NCBI
27	Lin Y, Gao H, Ai S, Eswarakumar JVP, Zhu Y, Chen C, Li T, Liu B, Jiang H, Liu Y, et al: FGFR2 mutations and associated clinical observations in two Chinese patients with Crouzon syndrome. Mol Med Rep. 16:5841–5846. 2017. View Article : Google Scholar : PubMed/NCBI
28	Lin Y, Li T, Gao H, Lian Y, Chen C, Zhu Y, Li Y, Liu B, Zhou W, Jiang H, et al: Bestrophin 1 gene analysis and associated clinical findings in a Chinese patient with Best vitelliform macular dystrophy. Mol Med Rep. 16:4751–4755. 2017. View Article : Google Scholar : PubMed/NCBI
29	Lin Y, Ai S, Chen C, Liu X, Luo L, Ye S, Liang X, Zhu Y, Yang H and Liu Y: Ala344Pro mutation in the FGFR2 gene and related clinical findings in one Chinese family with Crouzon syndrome. Mol Vis. 18:1278–1282. 2012.PubMed/NCBI
30	Burland TG: DNASTAR's Lasergene sequence analysis software. Methods Mol Biol. 132:71–91. 2000.
31	Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS and Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods. 7:248–249. 2010. View Article : Google Scholar : PubMed/NCBI
32	Kumar P, Henikoff S and Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 4:1073–1081. 2009. View Article : Google Scholar : PubMed/NCBI
33	Lin Y, Li T, Ma C, Gao H, Chen C, Zhu Y, Liu B, Lian Y, Huang Y, Li H, et al: Genetic variations in Bestrophin 1 and associated clinical findings in two Chinese patients with juvenile onset and adult onset best vitelliform macular dystrophy. Mol Med Rep. 17:225–233. 2018.
34	Ang A, Poulson AV, Goodburn SF, Richards AJ, Scott JD and Snead MP: Retinal detachment and prophylaxis in type 1 Stickler syndrome. Ophthalmology. 115:164–168. 2008. View Article : Google Scholar
35	Wang X, Jia X, Xiao X, Li S, Li J, Li Y, Wei Y, Liang X and Guo X: Mutation survey and genotype-phenotype analysis of COL2A1 and COL11A1 genes in 16 Chinese patients with Stickler syndrome. Mol Vis. 22:697–704. 2016.PubMed/NCBI
36	Vilaplana F, Muiños SJ, Nadal J, Elizalde J and Mojal S: Stickler syndrome. Epidemiology of retinal detachment. Arch Soc Esp Oftalmol. 90:264–268. 2015.In English, Spanish. View Article : Google Scholar : PubMed/NCBI
37	Antunes RB, Alonso N and Paula RG: Importance of early diagnosis of Stickler syndrome in newborns. J Plast Reconstr Aesthet Surg. 65:1029–1034. 2012. View Article : Google Scholar : PubMed/NCBI
38	Wilson MC, McDonald-McGinn DM, Quinn GE, Markowitz GD, LaRossa D, Pacuraru AD, Zhu X and Zackai EH: Long-term follow-up of ocular findings in children with Stickler's syndrome. Am J Ophthalmol. 122:727–728. 1996. View Article : Google Scholar : PubMed/NCBI
39	Watanabe Y, Ueda M and Adachi-Usami E: Retinal detachment in identical twins with Stickler syndrome type 1. Br J Ophthalmol. 80:976–981. 1996. View Article : Google Scholar : PubMed/NCBI
40	Bowling EL, Brown MD and Trundle TV: The Stickler syndrome: Case reports and literature review. Optometry. 71:177–182. 2000.PubMed/NCBI
41	De Keyzer TH, De Veuster I and Smets RM: Stickler syndrome: An underdiagnosed disease. Report of a family. Bull Soc Belge Ophtalmol. 45–49. 2011.PubMed/NCBI
42	Hoornaert KP, Vereecke I, Dewinter C, Rosenberg T, Beemer FA, Leroy JG, Bendix L, Björck E, Bonduelle M, Boute O, et al: Stickler syndrome caused by COL2A1 mutations: Genotype-phenotype correlation in a series of 100 patients. Eur J Hum Genet. 18:872–880. 2010. View Article : Google Scholar : PubMed/NCBI
43	Lee KH and Hayward P: Retrospective review of Stickler syndrome patients with cleft palate 1997–2004. ANZ J Surg. 78:764–766. 2008. View Article : Google Scholar : PubMed/NCBI
44	Parke DW: Stickler syndrome: Clinical care and molecular genetics. Am J Ophthalmol. 134:746–748. 2002. View Article : Google Scholar : PubMed/NCBI
45	Brown DM, Vandenburgh K, Kimura AE, Weingeist TA, Sheffield VC and Stone EM: Novel frameshift mutations in the procollagen 2 gene (COL2A1) associated with Stickler syndrome (hereditary arthro-ophthalmopathy). Hum Mol Genet. 4:141–142. 1995. View Article : Google Scholar : PubMed/NCBI
46	Yoshida S, Yamaji Y, Kuwahara R, Yoshida A, Hisatomi T, Ueno A and Ishibashi T: Novel mutation in exon 2 of COL2A1 gene in Japanese family with Stickler Syndrome type I. Eye (Lond). 20:743–745. 2006. View Article : Google Scholar
47	Higuchi Y, Hasegawa K, Yamashita M, Tanaka H and Tsukahara H: A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: A case report and review of the literature. J Med Case Rep. 11:2372017. View Article : Google Scholar : PubMed/NCBI
48	Fincham GS, Pasea L, Carroll C, McNinch AM, Poulson AV, Richards AJ, Scott JD and Snead MP: Prevention of retinal detachment in Stickler syndrome: The Cambridge prophylactic cryotherapy protocol. Ophthalmology. 121:1588–1597. 2014. View Article : Google Scholar : PubMed/NCBI
49	Kondo H, Matsushita I, Nagata T, Hayashi T, Kakinoki M, Uchio E, Kondo M, Ohji M and Kusaka S: Novel mutations in the COL2A1 gene in Japanese patients with Stickler syndrome. Hum Genome Var. 3:160182016. View Article : Google Scholar : PubMed/NCBI
50	Richards AJ, Laidlaw M, Meredith SP, Shankar P, Poulson AV, Scott JD and Snead MP: Missense and silent mutations in COL2A1 result in Stickler syndrome but via different molecular mechanisms. Hum Mutat. 28:6392007. View Article : Google Scholar : PubMed/NCBI