Human Genetics

, Volume 123, Issue 4, pp 371–378 | Cite as

Pax6 3′ deletion results in aniridia, autism and mental retardation

  • L. K. Davis
  • K. J. Meyer
  • D. S. Rudd
  • A. L. Librant
  • E. A. Epping
  • V. C. Sheffield
  • T. H. Wassink
Original Investigation

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.

References

  1. Azuma N, Yamada M (1998) Missense mutation at the C terminus of the PAX6 gene in ocular anterior segment anomalies. Invest Ophthalmol Vis Sci 39:828–830PubMedGoogle Scholar
  2. Azuma N, Nishina S, Yanagisawa H, Okuyama T, Yamada M (1996) PAX6 missense mutation in isolated foveal hypoplasia. Nat Genet 13:141–142PubMedCrossRefGoogle Scholar
  3. Azuma N, Hotta Y, Tanaka H, Yamada M (1998) Missense mutations in the PAX6 gene in aniridia. Invest Ophthalmol Vis Sci 39:2524–2528PubMedGoogle Scholar
  4. Azuma N et al (1999) Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies. Am J Hum Genet 65:656–663PubMedCrossRefGoogle Scholar
  5. Azuma N et al (2003) Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. Am J Hum Genet 72:1565–1570PubMedCrossRefGoogle Scholar
  6. 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 46:196–202PubMedCrossRefGoogle Scholar
  7. 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 161:463–469PubMedCrossRefGoogle Scholar
  8. Brown A, McKie M, van Heyningen V, Prosser J (1998) The human PAX6 mutation database. Nucleic Acids Res 26:259–264PubMedCrossRefGoogle Scholar
  9. 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):1074–1083PubMedCrossRefGoogle Scholar
  10. Chao LY, Mishra R, Strong LC, Saunders GF (2003) Missense mutations in the DNA-binding region and termination codon in PAX6. Hum Mutat 21:138–145PubMedCrossRefGoogle Scholar
  11. Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK (2006) A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 38:75–81PubMedCrossRefGoogle Scholar
  12. Crolla JA, van Heyningen V (2002) Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia. Am J Hum Genet 71:1138–1149PubMedCrossRefGoogle Scholar
  13. Dansault A et al (2007) Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities. Mol Vis 13:511–523PubMedGoogle Scholar
  14. Ellison-Wright Z et al (2004) Heterozygous PAX6 mutation, adult brain structure and fronto-striato-thalamic function in a human family. Eur J Neurosci 19:1505–1512PubMedCrossRefGoogle Scholar
  15. 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 25:447–461PubMedCrossRefGoogle Scholar
  16. Fischbach BV, Trout KL, Lewis J, Luis CA, Sika M (2005) WAGR syndrome: a clinical review of 54 cases. Pediatrics 116:984–988PubMedCrossRefGoogle Scholar
  17. 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 143:1802–1805PubMedGoogle Scholar
  18. 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 112:89–100PubMedCrossRefGoogle Scholar
  19. Hanson IM (2003) PAX6 and congenital eye malformations. Pediatr Res 54:791–796PubMedCrossRefGoogle Scholar
  20. Hever AM et al (2006) Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2. Clin Genet 69:459–470PubMedCrossRefGoogle Scholar
  21. 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 9:85–90PubMedCrossRefGoogle Scholar
  22. Iafrate AJ et al (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951PubMedCrossRefGoogle Scholar
  23. Kerjan G, Gleeson JG (2007) Genetic mechanisms underlying abnormal neuronal migration in classical lissencephaly. Trends Genet 23:623–630PubMedCrossRefGoogle Scholar
  24. 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 13:102–107PubMedCrossRefGoogle Scholar
  25. 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 265:462–477PubMedCrossRefGoogle Scholar
  26. Kleinjan DA et al (2006) Long-range downstream enhancers are essential for Pax6 expression. Dev Biol 299:563–581PubMedCrossRefGoogle Scholar
  27. 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 292:486–505PubMedCrossRefGoogle Scholar
  28. 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 97:13755–13759PubMedCrossRefGoogle Scholar
  29. Love J et al. (1998) A new set of primers for mutation analysis of the human PAX6 gene. Hum Mutat 12:128–34PubMedCrossRefGoogle Scholar
  30. Malandrini A et al (2001) PAX6 mutation in a family with aniridia, congenital ptosis, and mental retardation. Clin Genet 60:151–154PubMedCrossRefGoogle Scholar
  31. Mitchell TN et al (2003) Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol 53:658–663PubMedCrossRefGoogle Scholar
  32. 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 12:138PubMedCrossRefGoogle Scholar
  33. Nannya Y et al (2005) A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res 65:6071–6079PubMedCrossRefGoogle Scholar
  34. 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 130:3269–3281PubMedCrossRefGoogle Scholar
  35. Sebat J et al (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528PubMedCrossRefGoogle Scholar
  36. 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 16:325–332PubMedCrossRefGoogle Scholar
  37. Tang HK et al (1997) Functional analysis of paired box missense mutations in the PAX6 gene. Hum Mol Gen 6:381–386PubMedCrossRefGoogle Scholar
  38. Ticho BH et al (2006) Ocular findings in Gillespie-like syndrome: association with a new PAX6 mutation. Ophthalmic Genet 27:145–149PubMedCrossRefGoogle Scholar
  39. 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 67:1059–1074PubMedCrossRefGoogle Scholar
  40. Tzoulaki I, White IM, Hanson IM (2005) PAX6 mutations: genotype-phenotype correlations. BMC Genet 6:27PubMedCrossRefGoogle Scholar
  41. 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 44:787–790PubMedCrossRefGoogle Scholar
  42. van Heyningen V, Williamson KA (2002) PAX6 in sensory development. Hum Mol Genet 11:1161–1167PubMedCrossRefGoogle Scholar
  43. Williams PG, Hersh JH (1998) Brief report: the association of neurofibromatosis type 1 and autism. J Autism Dev Disord 28:567–571PubMedCrossRefGoogle Scholar
  44. Xu S et al (2007) In American Society of human genetics (San Diego, 2007)Google Scholar
  45. Zafeiriou DI, Ververi A, Vargiami E (2007) Childhood autism and associated comorbidities. Brain Dev 29:257–272PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • L. K. Davis
    • 1
    • 4
  • K. J. Meyer
    • 1
    • 4
  • D. S. Rudd
    • 1
  • A. L. Librant
    • 1
  • E. A. Epping
    • 1
  • V. C. Sheffield
    • 2
    • 3
    • 4
  • T. H. Wassink
    • 1
    • 4
  1. 1.Department of PsychiatryUniversity of Iowa Carver College of MedicineIowa CityUSA
  2. 2.Department of PediatricsUniversity of Iowa Carver College of MedicineIowa CityUSA
  3. 3.Howard Hughes Medical InstituteUniversity of IowaIowa CityUSA
  4. 4.Interdisciplinary Program In GeneticsUniversity of IowaIowa CityUSA

Personalised recommendations