Two Paired Box 6 mutations identified in Chinese patients with classic congenital aniridia and cataract

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

doi:10.3892/mmr.2018.9469

Two Paired Box 6 mutations identified in Chinese patients with classic congenital aniridia and cataract

Authors:
- Ying Lin
- Hongbin Gao
- Yi Zhu
- Chuan Chen
- Tao Li
- Bingqian Liu
- Cancan Lyu
- Ying Huang
- Haichun Li
- Qingxiu Wu
- Chenjin Jin
- Xiaoling Liang
- Xinhua Huang
- Lin Lu
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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: September 10, 2018 https://doi.org/10.3892/mmr.2018.9469
Pages: 4439-4445
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Congenital aniridia is a rare genetic disorder characterized by a variable degree of hypoplasia or absence of iris. It is frequently associated with keratopathy, cataract, juvenile‑onset glaucoma and foveal and optic nerve hypoplasia. Mutations in the Paired Box 6 (PAX6) gene on chromosome 11p13 have been demonstrated to cause aniridia. The aim of the present study was to investigate the genetic variations of PAX6 in two sporadic patients from southern China with classic congenital aniridia and cataract. Complete ophthalmic and physical examinations were performed, including best‑corrected visual acuity, intraocular pressure, slit‑lamp examination, fundus examination, optical coherence tomography, ultrasound biomicroscopy, and Pentacam scanning. Genomic DNA was extracted from leukocytes of peripheral blood collected from the two patients, their unaffected parents and 200 unrelated control subjects from the same population. Exons 4‑13 of the PAX6 gene were amplified by polymerase chain reaction and sequenced directly. Patient 1 was affected with aniridia accompanied by congenital cataract and nystagmus. A novel heterozygous PAX6 frameshift mutation c.277delG (p.Glu93SerfsX31) in exon 6 was identified in this patient. Patient 2 was presented with aniridia, congenital cataract, lens subluxation and glaucoma. A recurrent nonsense mutation c.718C>T (p.Arg240X) in exon 9 was identified in this patient. The present results expand the mutation spectrum of PAX6 and will be valuable for genetic counseling in the affected families. Additionally, the identification of these mutations reiterates the importance of PAX6 in ocular development and sheds light on the pathogenesis of congenital aniridia.

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1	Hanson IM, Seawright A, Hardman K, Hodgson S, Zaletayev D, Fekete G and van Heyningen V: PAX6 mutations in aniridia. Hum Mol Genet. 2:915–920. 1993. View Article : Google Scholar : PubMed/NCBI
2	Chen JH, Lin W, Sun G, Huang C, Huang Y, Chen H, Pang CP and Zhang M: A novel PAX6 deletion in a Chinese family with congenital aniridia. Mol Vis. 18:989–995. 2012.PubMed/NCBI
3	Fischbach BV, Trout KL, Lewis J, Luis CA and Sika M: WAGR syndrome: A clinical review of 54 cases. Pediatrics. 116:984–988. 2005. View Article : Google Scholar : PubMed/NCBI
4	Sarsfield JK: The syndrome of congenital cerebellar ataxia, aniridia and mental retardation. Dev Med Child Neurol. 13:508–511. 1971. View Article : Google Scholar : PubMed/NCBI
5	Hingorani M and Moore A: AniridiaGeneReviews^® [Internet]. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K and Amemiya A: University of Washington; Seattle, WA: pp. 1993–2018
6	Calvão-Pires P, Santos-Silva R, Falcão-Reis F and Rocha-Sousa A: Congenital aniridia: Clinic, genetics, therapeutics, and prognosis. Int Sch Res Notices. 2014:3053502014.PubMed/NCBI
7	Lee H, Khan R and O'Keefe M: Aniridia: Current pathology and management. Acta Ophthalmol. 86:708–715. 2008. View Article : Google Scholar : PubMed/NCBI
8	Yokoi T, Nishina S, Fukami M, Ogata T, Hosono K, Hotta Y and Azuma N: Genotype-phenotype correlation of PAX6 gene mutations in aniridia. Hum Genome Var. 3:150522016. View Article : Google Scholar : PubMed/NCBI
9	Jordan T, Hanson I, Zaletayev D, Hodgson S, Prosser J, Seawright A, Hastie N and van Heyningen V: The human PAX6 gene is mutated in two patients with aniridia. Nat Genet. 1:328–332. 1992. View Article : Google Scholar : PubMed/NCBI
10	Axton R, Hanson I, Danes S, Sellar G, van Heyningen V and Prosser J: The incidence of PAX6 mutation in patients with simple aniridia: An evaluation of mutation detection in 12 cases. J Med Genet. 34:279–286. 1997. View Article : Google Scholar : PubMed/NCBI
11	Ton CC, Hirvonen H, Miwa H, Weil MM, Monaghan P, Jordan T, van Heyningen V, Hastie ND, Meijers-Heijboer H, Drechsler M, et al: Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell. 67:1059–1074. 1991. View Article : Google Scholar : PubMed/NCBI
12	Halder G, Callaerts P and Gehring WJ: Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science. 267:1788–1792. 1995. View Article : Google Scholar : PubMed/NCBI
13	Czerny T, Schaffner G and Busslinger M: DNA sequence recognition by Pax proteins: Bipartite structure of the paired domain and its binding site. Genes Dev. 7:2048–2061. 1993. View Article : Google Scholar : PubMed/NCBI
14	Mishra R, Gorlov IP, Chao LY, Singh S and Saunders GF: PAX6, paired domain influences sequence recognition by the homeodomain. J Biol Chem. 277:49488–49494. 2002. View Article : Google Scholar : PubMed/NCBI
15	Xu HE, Rould MA, Xu W, Epstein JA, Maas RL and Pabo CO: Crystal structure of the human Pax6 paired domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding. Genes Dev. 13:1263–1275. 1999. View Article : Google Scholar : PubMed/NCBI
16	Singh S, Chao LY, Mishra R, Davies J and Saunders GF: Missense mutation at the C-terminus of PAX6 negatively modulates homeodomain function. Hum Mol Genet. 10:911–918. 2001. View Article : Google Scholar : PubMed/NCBI
17	Coutinho P, Pavlou S, Bhatia S, Chalmers KJ, Kleinjan DA and van Heyningen V: Discovery and assessment of conserved Pax6 target genes and enhancers. Genome Res. 21:1349–1359. 2011. View Article : Google Scholar : PubMed/NCBI
18	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.PubMed/NCBI
19	Huang X, Lin Y, Chen C, Zhu Y, Gao H, Li T, Liu B, Lyu C, Huang Y, Wu Q, et al: Targeted next-generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment. Int J Mol Med. 42:1819–1826. 2018.PubMed/NCBI
20	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
21	Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF and bden Dunnen JT: LOVD v. 2.0: the next generation in gene variant databases. Hum Mutat. 32:557–563. 2011. View Article : Google Scholar : PubMed/NCBI
22	Azuma N, Hotta Y, Tanaka H and Yamada M: Missense mutations in the PAX6 gene in aniridia. Invest Ophthalmol Vis Sci. 39:2524–2528. 1998.PubMed/NCBI
23	Dharmaraj N, Reddy A, Kiran V, Mandal A, Panicker S and Chakrabarti S: PAX6 gene mutations and genotype-phenotype correlations in sporadic cases of aniridia from India. Ophthalmic Genet. 24:161–165. 2003. View Article : Google Scholar : PubMed/NCBI
24	Villarroel CE, Villanueva-Mendoza C, Orozco L, Alcántara-Ortigoza MA, Jiménez DF, Ordaz JC and González-del Angel A: Molecular analysis of the PAX6 gene in Mexican patients with congenital aniridia: Report of four novel mutations. Mol Vis. 14:1650–1658. 2008.PubMed/NCBI
25	Park SH, Kim MS, Chae H, Kim Y and Kim M: Molecular analysis of the PAX6 gene for congenital aniridia in the Korean population: Identification of four novel mutations. Mol Vis. 18:488–494. 2012.PubMed/NCBI
26	Pérez-Solórzano S, Chacón-Camacho OF, Astiazarán MC, Ledesma-Gil G and Zenteno JC: PAX6 allelic heterogeneity in Mexican congenital aniridia patients: Expanding the mutational spectrum with Seven novel pathogenic variants. Clin Exp Ophthalmol. 45:875–883. 2017. View Article : Google Scholar : PubMed/NCBI
27	Angmo D, Jha B and Panda A: Congenital aniridia. J Curr Glaucoma Pract. 5:01–13. 2011.
28	Neuhann IM and Neuhann TF: Cataract surgery and aniridia. Curr Opin Ophthalmol. 21:60–64. 2010. View Article : Google Scholar : PubMed/NCBI
29	Hashmani S, Haider SI, Khatri B and Rind GK: Management of Aniridia with Ectopia Lentis. Pak J Ophthalmol. 31:48–50. 2015.
30	Parekh M, Poli B, Ferrari S, Teofili C and Ponzin D: Aniridia. Springer; New York, NY: 2015, View Article : Google Scholar
31	Adeoti CO, Afolabi AA, Ashaye AO and Adeoye AO: Bilateral sporadic aniridia: Review of management. Clin Ophthalmol. 4:1085–1089. 2010. View Article : Google Scholar : PubMed/NCBI
32	Brémond-Gignac D: Glaucoma in aniridia. J Fr Ophtalmol. 30:196–199. 2007.(In French). View Article : Google Scholar : PubMed/NCBI
33	Park SH, Park YG, Lee MY and Kim MS: Clinical features of Korean patients with congenital aniridia. Korean J Ophthalmol. 24:291–296. 2010. View Article : Google Scholar : PubMed/NCBI