Abstract
The PAX6 gene is a transcription factor expressed early in development, predominantly in the eye, brain and gut. It is well known that mutations in PAX6 may result in aniridia, Peter’s anomaly and kertatisis. Here, we present mutation analysis of a patient with aniridia, autism and mental retardation. We identified and characterized a 1.3 Mb deletion that disrupts PAX6 transcriptional activity and deletes additional genes expressed in the brain. Our findings provide continued evidence for the role of PAX6 in neural phenotypes associated with aniridia.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Azuma N, Yamada M (1998) Missense mutation at the C terminus of the PAX6 gene in ocular anterior segment anomalies. Invest Ophthalmol Vis Sci 39:828–830
Azuma N, Nishina S, Yanagisawa H, Okuyama T, Yamada M (1996) PAX6 missense mutation in isolated foveal hypoplasia. Nat Genet 13:141–142
Azuma N, Hotta Y, Tanaka H, Yamada M (1998) Missense mutations in the PAX6 gene in aniridia. Invest Ophthalmol Vis Sci 39:2524–2528
Azuma N et al (1999) Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies. Am J Hum Genet 65:656–663
Azuma N et al (2003) Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. Am J Hum Genet 72:1565–1570
Bamiou DE et al (2007a Auditory and verbal working memory deficits in a child with congenital aniridia due to a PAX6 mutation. Int J Audiol 46:196–202
Bamiou DE et al (2007b Auditory interhemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med 161:463–469
Brown A, McKie M, van Heyningen V, Prosser J (1998) The human PAX6 mutation database. Nucleic Acids Res 26:259–264
Cideciyan AV et al (2007) Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Hum Mutat 28(11):1074–1083
Chao LY, Mishra R, Strong LC, Saunders GF (2003) Missense mutations in the DNA-binding region and termination codon in PAX6. Hum Mutat 21:138–145
Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK (2006) A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 38:75–81
Crolla JA, van Heyningen V (2002) Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia. Am J Hum Genet 71:1138–1149
Dansault A et al (2007) Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities. Mol Vis 13:511–523
Ellison-Wright Z et al (2004) Heterozygous PAX6 mutation, adult brain structure and fronto-striato-thalamic function in a human family. Eur J Neurosci 19:1505–1512
Fantes JA et al (1995) A high-resolution integrated physical, cytogenetic, and genetic map of human chromosome 11: distal p13 to proximal p15.1. Genomics 25:447–461
Fischbach BV, Trout KL, Lewis J, Luis CA, Sika M (2005) WAGR syndrome: a clinical review of 54 cases. Pediatrics 116:984–988
Graziano C et al (2007) A de novo nonsense mutation of PAX6 gene in a patient with aniridia, ataxia, and mental retardation. Am J Med Genet A 143:1802–1805
Griffin C, Kleinjan DA, Doe B, van Heyningen V (2002) New 3′ elements control Pax6 expression in the developing pretectum, neural retina and olfactory region. Mech Dev 112:89–100
Hanson IM (2003) PAX6 and congenital eye malformations. Pediatr Res 54:791–796
Hever AM et al (2006) Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2. Clin Genet 69:459–470
Heyman I et al (1999) Psychiatric disorder and cognitive function in a family with an inherited novel mutation of the developmental control gene PAX6. Psychiatr Genet 9:85–90
Iafrate AJ et al (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951
Kerjan G, Gleeson JG (2007) Genetic mechanisms underlying abnormal neuronal migration in classical lissencephaly. Trends Genet 23:623–630
Kleinjan DA, Seawright A, Elgar G, van Heyningen V (2002) Characterization of a novel gene adjacent to PAX6, revealing synteny conservation with functional significance. Mamm Genome 13:102–107
Kleinjan DA, Seawright A, Childs AJ, van Heyningen V (2004) Conserved elements in Pax6 intron 7 involved in (auto) regulation and alternative transcription. Dev Biol 265:462–477
Kleinjan DA et al (2006) Long-range downstream enhancers are essential for Pax6 expression. Dev Biol 299:563–581
Kim J, Lauderdale JD (2006) Analysis of Pax6 expression using a BAC transgene reveals the presence of a paired-less isoform of Pax6 in the eye and olfactory bulb. Dev Biol 292:486–505
Lauderdale JD, Wilensky JS, Oliver ER, Walton DS, Glaser T (2000) 3’ deletions cause aniridia by preventing PAX6 gene expression. Proc Natl Acad Sci USA 97:13755–13759
Love J et al. (1998) A new set of primers for mutation analysis of the human PAX6 gene. Hum Mutat 12:128–34
Malandrini A et al (2001) PAX6 mutation in a family with aniridia, congenital ptosis, and mental retardation. Clin Genet 60:151–154
Mitchell TN et al (2003) Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol 53:658–663
Neuner-Jehle M, Munier F, Kobetz A, Sahly I, Uteza Y, Mermoud A, Schorderet DF, Dufier JL, Abitbol M (1998) Identification of novel PAX6 mutations in two families with bilateral aniridia. Mutations in brief no. 167. Online. Hum Mutat 12:138
Nannya Y et al (2005) A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res 65:6071–6079
Scardigli R, Baumer N, Gruss P, Guillemot F, Le Roux I (2003) Direct and concentration-dependent regulation of the proneural gene Neurogenin2 by Pax6. Development 130:3269–3281
Sebat J et al (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528
Sheffield VC, Beck JS, Kwitek AE, Sandstrom DW, Stone EM (1993) The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics 16:325–332
Tang HK et al (1997) Functional analysis of paired box missense mutations in the PAX6 gene. Hum Mol Gen 6:381–386
Ticho BH et al (2006) Ocular findings in Gillespie-like syndrome: association with a new PAX6 mutation. Ophthalmic Genet 27:145–149
Ton CC, Hirvonen H, Miwa H, Weil MM, Monaghan P, Jordan T, van Heyningen V, Hastie ND, Meijers-Heijboer H, Drechsler M et al (1991) Positional cloning and characterization of a paired box and homeobox-containing gene from the aniridia region. Cell 67:1059–1074
Tzoulaki I, White IM, Hanson IM (2005) PAX6 mutations: genotype-phenotype correlations. BMC Genet 6:27
van Heyningen V, Hoovers JM, de Kraker J, Crolla JA (2007) Raised risk of Wilms tumour in patients with aniridia and submicroscopic WT1 deletion. J Med Genet 44:787–790
van Heyningen V, Williamson KA (2002) PAX6 in sensory development. Hum Mol Genet 11:1161–1167
Williams PG, Hersh JH (1998) Brief report: the association of neurofibromatosis type 1 and autism. J Autism Dev Disord 28:567–571
Xu S et al (2007) In American Society of human genetics (San Diego, 2007)
Zafeiriou DI, Ververi A, Vargiami E (2007) Childhood autism and associated comorbidities. Brain Dev 29:257–272
Acknowledgments
We would like to acknowledge the family that participated in this research. We would also like to thank Tyler Rassmusen for his help in preparation of the manuscript. This work was supported by the Hilibrand Foundation and by NIH Predoctoral Training Grant (2T32GM008629) awarded to Lea Davis.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Davis, L.K., Meyer, K.J., Rudd, D.S. et al. Pax6 3′ deletion results in aniridia, autism and mental retardation. Hum Genet 123, 371–378 (2008). https://doi.org/10.1007/s00439-008-0484-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-008-0484-x