Genetic aspects of congenital aniridia
T.A. VASILYEVA1, N.A. POZDEYEVA², A.A. VOSKRESENSKAYA², O.V. KHLEBNIKOVA1, R.A. ZINCHENKO1, 3, 4, E.K. GINTER1, 5
1Center for Medical Genetics of the RAMS, 1 Moskvorechye St., Moscow, Russian Federation, 115478
2Cheboksary branch of Eye Microsurgery Federal State Institution named after S.N. Fyodorov, 10 pr. Traktorostroiteley, Cheboksary, Russian Federation, 428028
3Scientific and Practical Center of Medical Care for Children, 38 Aviatorov St., Moscow, Russian Federation, 119620
4Russian National Research Medical University named after N.I. Pirogov, 1 Ostrovityanova St., Moscow, Russian Federation, 117997
5Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya St., Moscow, Russian Federation, 125993
Vasilyeva T.A. — researcher of the Laboratory of Genetic Epidemiology, tel. +7-915-287-30-96, e-mail: vasilyeva_debrie@mail.ru
Pozdeyeva N.A. — D. Med. Sc., Deputy Director for Science, tel.: (8352) 36-91-81, +7-917-079-93-40, e-mail: npozdeeva@mail.ru
Voskresenskaya A.A. — ophthalmologist of the Department of Ambulant Surgery and Conservative Treatment, tel. тел. (8352) 36-90-00, e-mail: vsolaris@mail.ru
Khlebnikova O.V. — D. Med. Sc., leading researcher of the Laboratory of Genetic Epidemiology, ophthalmogenetician, tel. +7-903-565-43-16, e-mail: khlebnikova@med-gen.ru
Zinchenko R.A. – D. Med. Sc., Professor, Head of the Laboratory of Genetic Epidemiology, tel.: (499) 324-12-24, +7-925-232-04-63, e-mail: renazinchenko@mail.ru
Ginter E.K. — Doctor of Biology, Professor, Academician of the Russian Academy of Sciences, Director, tel. (499) 612-86-07, e-mail: ekginter@mail.ru
Aniridia is a complex progressive congenital disorder affecting all structures of the eye. It is characterized by a total absence or partial hypoplasia of iris, fovea and optic nerve hypoplasia, nistagmus, and cornea opacity. It may be accompanied by cataracts, glaucoma and additional developmental defects of the brain, olfactory system and pancreas. Aniridia has an autosomal dominant inheritance with complete penetrance and variable expressiveness. Heterozygous mutations in the PAX6 gene are the cause of congenital aniridia. PAX6 is one of the key embryogenesis regulators, it is conserved in all bilateral-symmetrical animals. PAX6 coordinates and synchronies the coherent morphogenesis processes in cells of different origin, as well as forms the ability of future eye tissues to respond to inductive signals. Mutations in the gene lead to complex damage of all structures of the eye. There are more than 600 different known mutations in the PAX6 gene. About 72% of all mutations associated with aniridia result in premature stop codon. Microdeletions of chromosome region 11p13 are found in about a third of the detected genetic defects in aniridia. Although aniridia associated mutations are found in PAX6 in more than 95% of cases, complex aniridia phenotypes might overlap with clinical phenotypes caused by changes in other genes (e.g. FOXC1, PITX2, PITX3). Differential exclusion of WAGR syndrome, Axenfeld-Rieger syndrome, Peters anomality and other rarer syndromes (according to the OMIM database, 17 syndromes) is to be carried out. 85% of aniridia cases occur as an isolated malformation, in about 13% of cases aniridia is a part of the WAGR syndrome, and in 2-5% of cases — a part of rarer syndromes.
Key words: congenital aniridia, complex defects of all eye structures, the PAX6 gene mutations, differential exclusion of WAGR syndrome.
REFERENCES
- Crolla J., van Heyningen V. Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia. Am J Hum Genet., 2002, vol. 71, pp. 1138-49.
- Gramer, Reiter C., Gramer G. Glaucoma and frequency of ocular and general diseases in 30 patients with aniridia: a clinical study. Eur J Ophthalmol., 2012, vol. 22, pp. 104-10.
- Hingorani J., Moore A. Initial Posting: May 20, 2003; last update: November 14, 2013.
- Hingorani M., Hanson I., van Heyningen V. Aniridia. Eur J Hum Genet., 2012, 20, pp. 1011-1017.
- Okamoto, Nakano S., Okamoto C., Hommura S., Oshika T. Ultrasound biomicroscopic findings in aniridia. American Journal of Ophthalmology, 2004, vol. 137, pp. 858–862.
- Bamiou D. Auditory and verbal working memory deficits in a child with congenital aniridia due to a PAX6 mutation. International journal of audiology, 2007, vol. 46, pp. 196-202.
- Thompson P., Mitchell T., Free S., Williamson K. et al. Cognitive functioning in humans with mutations of the PAX6 gene. Neurology, 2004, vol. 7, pp. 1216-1218.
- Chen, Zang X., Sun D., Wang Y. et al. Mutation analysis of paired box 6 gene in inherited aniridia in northern China. Mol Vis., 2013, vol. 19, pp. 1169-1177.
- Lee H., Khan R., O’Keefe M. Aniridia: current pathology and management. Acta Ophthalmol., 2008, vol. 86, pp. 708-715.
- Lyons L., Martha A, Mintz, Hittner H. et al. Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome 11p13. Genomics, 1992, vol. 13, pp. 925-930.
- Kumar, Moses K. Eye specification in Drosophila: perspectives and implications. Semin Cell Dev Biol., 2001, vol. 12, pp. 469-74.
- Cvekl A., Tamm E. Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases. Bio Essays., 2004, vol. 26, pp. 374-386.
- Gregory-Evans, Wang X., Wasan K., Zhao J. et al. Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects. J Clin Invest., 2014, vol. 124, pp. 111-116.
- Kokotas H., Petersen M. Clinical and molecular aspects of aniridia. Clin Genet., 2010, vol. 77, pp. 409-20.
- Fuhrmann S. Eye morphogenesis and patterning of the optic vesicle. Curr Top Dev Biol., 2010, vol. 93, pp. 61-84.
- Liu H., Xu S., Wang Y., Mazerolle C. et al. Ciliary margin transdifferentiation from neural retina is controlled by canonical Wnt signaling. Dev Biol., 2007, vol. 308, pp. 54-67.
- Zhang , Wang P., Li S., Xiao X. et al. Mutation spectrum of PAX6 in Chinese patients with aniridia. Mol Vis., 2011, vol. 17, pp. 2139-47.
- Tzoulaki I., White , Hanson I. PAX6 mutations: genotype-phenotype correlations. BMC Genet., 2005., doi:10.1186/1471-2156-6-27.
- Grønskov, Olsen J., Sand A., Pedersen W. et al. Population-based risk estimates of Wilms tumor in sporadic aniridia. Human Genetics, 2001, vol. 109, pp. 11-18.
- van Heyningen, Hoovers J., de Kraker J., Crolla J. Raised risk of Wilms tumour in patients with aniridia and submicroscopic WT1 deletion. J Med Genet., 2007, vol. 44, pp. 787-790.
- Wawrocka , Sikora A., Kuszel L., Krawczynsk M. 11p13 deletions can be more frequent than the PAX6 gene point mutations in Polish patients with aniridia. J Appl Genet., 2013, vol. 54, pp. 345-51.
- Schilter, Reis L., Schneider A., Bardakjian T. et al. Whole-genome copy number variation analysis in anophthalmia and microphthalmia. Clin Genet., 2013, vol. 84, pp. 473-481.
- Skeens H., Brooks B., Holland E. Congenital Aniridia Variant: Minimally Abnormal Irides with Severe Limbal Stem Cell Deficiency. Ophthalmology, 2011, vol. 118, pp. 1260-1264.
- Azuma N., Yamaguchi Y., Handa H., Tadokoro K. et al. Mutations of the PAX6 Gene Detected in Patients with a Variety of Optic-Nerve Malformations. American Journal of Human Genetics, 2003, vol. 72, pp. 1565-1570.
- Ito Y., Footz T., Berry F., Mirzayans F., et al. Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. Invest Ophthalmol Vis Sci., 2009, vol. 50, pp. 3573-9.
- Sahel-A., Marazova K. Toward postnatal reversal of ocular congenital malformations. J Clin Invest., 2014, vol. 124, pp. 81-84.