Objective To identify the disease causative mutation in a Chinese family with congenital aniridia and to characterize its clinical phenotypes. Methods This was a case series study. Eight participants were recruited from the index family, including 3 patients, 2 asymptomatic siblings, and 3 spouses. All participants underwent detailed ophthalmic examinations. Peripheral blood samples were taken from all family members for DNA extraction. All coding and exon-intronic boundary regions of the PAX6 gene were amplified and sequenced to identify the disease causative mutation for this family. Results PAX6 c.357+5G>A, a heterozygous mutation located at the boundary region of exon 7 and intron 7, was identified as the disease causative mutation for this family. Bioinformatics analysis indicated that this mutation would cause the elimination of the regular splice-site and generate the truncated protein p.Ser121Asnfs*30. All three patients in this family presented with iris hypoplasia. Patients were also associated with other ocular abnormalities, including ptosis, cataract, glaucoma, vitreous opacities, reduced visual acuity, and nystagmus. Conclusion A heterozygousmutation of PAX6 c.357+5G>A causes aniridia and its associated ocular phenotypes, including ptosis, cataract, glaucoma, vitreous opacities, reduced visual acuity, and nystagmus, in the present family.
张秀梅,陈雪,高翔,赵堪兴,赵晨. 一先天性无虹膜家系PAX6基因遗传筛查及临床表型[J]. 中华眼视光学与视觉科学杂志, 2016, 18(3): 160-164.
Zhang Xiumei*,Chen Xue,Gao Xiang,Zhao Kanxing,Zhao Chen. A PAX6 gene mutation causes aniridia in a Chinese family. Chinese Journal of Optometry Ophthalmology and Visual science, 2016, 18(3): 160-164. DOI: 10.3760/cma.j.issn.1674-845X.2016.03.007
Zhang X, Tong Y, Xu W, et al. Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients[J]. Eye (Lond),2011,25(12):1581-1589. DOI:10.1038/eye.2011.215.
[2]
Schanilec P, Biernacki R. Aniridia: a comparative overview[J]. Am Orthopt J,2014,64:98-104. DOI:10.3368/aoj.64.1.98.
[3]
Hood MP, Kerr NC, Smaoui N, et al. Abnormal cone ERGs in a family with congenital nystagmus and photophobia harboring a p.X423Lfs mutation in the PAX6 gene[J]. Doc Ophthalmol,2015, 130(2):157-164. DOI:10.1007/s10633-014-9477-3.
[4]
Scott DA, Cooper ML, Stankiewicz P, et al. Congenital diaphragmatic hernia in WAGR syndrome[J]. Am J Med Genet A,2005,134(4):430-433. DOI:10.1002/ajmg.a.30654.
[5]
Francke U, Holmes LB, Atkins L, et al. Aniridia-Wilms′ tumor association: evidence for specific deletion of 11p13[J]. Cytogenet Cell Genet,1979,24(3):185-192. DOI:10.1159/000131375.
[6]
Glaser T, Walton DS, Maas RL. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene[J]. Nat Genet,1992,2(3):232-239. DOI:10.1038/ng1192-232.
[7]
Zhao C, Lu S, Zhou X, et al. A novel locus (RP33) for autosomal dominant retinitis pigmentosa mapping to chromosomal region 2cen-q12.1[J]. Hum Genet,2006,119(6):617-623. DOI:10. 1007/s00439-006-0168-3.
[8]
Jin C, Wang Q, Li J, et al. A recurrent PAX6 mutation is associated with aniridia and congenital progressive cataract in a Chinese family[J]. Mol Vis,2012,18:465-470.
[9]
Yan N, Zhao Y, Wang Y, et al. Molecular genetics of familial nystagmus complicated with cataract and iris anomalies[J]. Mol Vis,2011,17:2612-2617.
[10]
Sun J, Rockowitz S, Xie Q, et al. Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development[J]. Nucleic Acids Res,2015,43(14):6827-6846. DOI:10.1093/nar/gkv589.
[11]
Manuel MN, Mi D, Mason JO, et al. Regulation of cerebral cortical neurogenesis by the Pax6 transcription factor[J]. Front Cell Neurosci,2015,9:70. DOI:10.3389/fncel.2015.00070.
[12]
Kim YJ, Bahn M, Kim YH, et al. Xenopus laevis FGF receptor substrate 3 (XFrs3) is important for eye development and mediates Pax6 expression in lens placode through its Shp2-binding sites[J]. Dev Biol,2015,397(1):129-139. DOI:10.1016/j.ydbio.2014.10. 019.
[13]
Mayes DA, Hu Y, Teng Y, et al. PAX6 suppresses the invasiveness of glioblastoma cells and the expression of the matrix metalloproteinase-2 gene[J]. Cancer Res,2006,66(20):9809-9817. DOI:10.1158/0008-5472.
[14]
Lang D, Mascarenhas JB, Powell SK, et al. PAX6 is expressed in pancreatic adenocarcinoma and is downregulated during induction of terminal differentiation[J]. Mol Carcinog,2008,47(2):148-156. DOI:10.1002/mc.20375.
[15]
Zhong X, Li Y, Peng F, et al. Identification of tumorigenic retinal stem-like cells in human solid retinoblastomas[J]. Int J Cancer,2007,121(10):2125-2131. DOI:10.1002/ijc.22880.
[16]
Smith JE, Baker KE. Nonsense-mediated RNA decay-a switch and dial for regulating gene expression[J]. Bioessays,2015,37(6):612-623. DOI:10.1002/bies.201500007.
[17]
Tzoulaki I, White IM, Hanson IM. PAX6 mutations: genotype-phenotype correlations[J]. BMC Genet,2005,6:27. DOI:10.1186/1471-2156-6-27.
[18]
Zhao X, Yue W, Zhang L, et al. Downregulation of PAX6 by shRNA inhibits proliferation and cell cycle progression of human non-small cell lung cancer cell lines[J]. PLoS One,2014,9(1):e85738. DOI:10.1371/journal.pone.0085738.
[19]
Xie Q, Yang Y, Huang J, et al. Pax6 interactions with chromatin and identification of its novel direct target genes in lens and forebrain[J]. PLoS One,2013,8(1):e54507. DOI:10.1371/journal.pone.0054507.
[20]
Machon O, Kreslova J, Ruzickova J, et al. Lens morphogenesis is dependent on Pax6-mediated inhibition of the canonical Wnt/beta-catenin signaling in the lens surface ectoderm[J]. Genesis,2010,48(2):86-95. DOI:10.1002/dvg.20583.
[21]
Davis J, Piatigorsky J. Overexpression of Pax6 in mouse cornea directly alters corneal epithelial cells: changes in immune function, vascularization, and differentiation[J]. Invest Ophthalmol Vis Sci,2011,52(7):4158-4168. DOI:10.1167/iovs.10-6726.
浙公网安备 33030202001892号