Human Genetics

, Volume 128, Issue 1, pp 51–60

Use of genome-wide SNP homozygosity mapping in small pedigrees to identify new mutations in VSX2 causing recessive microphthalmia and a semidominant inner retinal dystrophy

  • Sibel Ugur Iseri
  • Alexander W. Wyatt
  • Gudrun Nürnberg
  • Christian Kluck
  • Peter Nürnberg
  • Graham E. Holder
  • Ed Blair
  • Alison Salt
  • Nicola K. Ragge
Original Investigation

Abstract

Mutations in the visual system homeobox 2 gene (VSX2, also known as CHX10), which encodes a retinal transcription factor from the paired homeobox family, have been implicated in recessive isolated microphthalmia. In this study, we use genome-wide single nucleotide polymorphism homozygosity mapping in unrelated small consanguineous pedigrees and a candidate gene approach to identify three further causative VSX2 mutations (two novel and one previously reported). All affected individuals with homozygous mutations had bilateral anophthalmia or severe microphthalmia with absent vision. In addition, we identified a novel inner retinal dystrophy in two carrier parents suggesting a semidominant effect for this particular VSX2 mutation. A further study of individuals with retinal degenerative conditions may reveal a causative role for heterozygous mutations in VSX2.

Supplementary material

439_2010_823_MOESM1_ESM.doc (175 kb)
Supplementary material (DOC 175 kb)

References

  1. Abecasis G, Cherny S, Cookson W, Cardon L (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101CrossRefPubMedGoogle Scholar
  2. Aligianis I, Johnson C, Gissen P, Chen D, Hampshire D, Hoffmann K, Maina E, Morgan N, Tee L, Morton J, Ainsworth J, Horn D, Rosser E, Cole T, Stolte-Dijkstra I, Fieggen K, Clayton-Smith J, Mégarbané A, Shield J, Newbury-Ecob R, Dobyns W, Graham JJ, Kjaer K, Warburg M, Bond J, Trembath R, Harris L, Takai Y, Mundlos S, Tannahill D, Woods C, Maher E (2005) Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet 37:221–223CrossRefPubMedGoogle Scholar
  3. Bakrania P, Robinson D, Bunyan D, Salt A, Martin A, Crolla J, Wyatt A, Fielder A, Ainsworth J, Moore A, Read S, Uddin J, Laws D, Pascuel-Salcedo D, Ayuso C, Allen L, Collin J, Ragge N (2007) SOX2 anophthalmia syndrome: 12 new cases demonstrating broader phenotype and high frequency of large gene deletions. Br J Ophthalmol 91:1471–1476CrossRefPubMedGoogle Scholar
  4. Bakrania P, Efthymiou M, Klein J, Salt A, Bunyan D, Wyatt A, Ponting C, Martin A, Williams S, Lindley V, Gilmore J, Restori M, Robson A, Neveu M, Holder G, Collin J, Robinson D, Farndon P, Johansen-Berg H, Gerrelli D, Ragge N (2008) Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet 82:304–319CrossRefPubMedGoogle Scholar
  5. Barabino S, Spada F, Cotelli F, Boncinelli E (1997) Inactivation of the zebrafish homologue of Chx10 by antisense oligonucleotides causes eye malformations similar to the ocular retardation phenotype. Mech Dev 63:133–143CrossRefPubMedGoogle Scholar
  6. Bar-Yosef U, Abuelaish I, Harel T, Hendler N, Ofir R, Birk O (2004) CHX10 mutations cause non-syndromic microphthalmia/anophthalmia in Arab and Jewish kindreds. Hum Genet 115:302–309CrossRefPubMedGoogle Scholar
  7. Bessant D, Khaliq S, Hameed A, Anwar K, Mehdi S, Payne A, Bhattacharya S (1998) A locus for autosomal recessive congenital microphthalmia maps to chromosome 14q32. Am J Hum Genet 62:1113–1116CrossRefPubMedGoogle Scholar
  8. Burkitt Wright E, Perveen R, Bowers N, Ramsden S, McCann E, O’Driscoll M, Lloyd I, Clayton-Smith J, Black G (2010) VSX2 in microphthalmia: a novel splice site mutation producing a severe microphthalmia phenotype. Br J Ophthalmol 94:386–388CrossRefPubMedGoogle Scholar
  9. Burmeister M, Novak J, Liang M, Basu S, Ploder L, Hawes N, Vidgen D, Hoover F, Goldman D, Kalnins V, Roderick T, Taylor B, Hankin M, McInnes R (1996) Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat Genet 12:376–384CrossRefPubMedGoogle Scholar
  10. Campbell H, Holmes E, MacDonald S, Morrison D, Jones I (2002) A capture–recapture model to estimate prevalence of children born in Scotland with developmental eye defects. J Cancer Epidemiol Prev 7:21–28CrossRefPubMedGoogle Scholar
  11. Chow RL, Snow B, Novak J, Looser J, Freund C, Vidgen D, Ploder L, McInnes RR (2001) Vsx1, a rapidly evolving paired-like homeobox gene expressed in cone bipolar cells. Mech Dev 109:315–322CrossRefPubMedGoogle Scholar
  12. Clark A, Yun S, Veien E, Wu Y, Chow R, Dorsky R, Levine E (2008) Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina. Brain Res 1192:99–113CrossRefPubMedGoogle Scholar
  13. Dhomen N, Balaggan K, Pearson R, Bainbridge J, Levine E, Ali R, Sowden J (2006) Absence of chx10 causes neural progenitors to persist in the adult retina. Invest Ophthalmol Vis Sci 47:386–396CrossRefPubMedGoogle Scholar
  14. Dyer MA, Livesey FJ, Cepko CL, Oliver G (2003) Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat Genet 34:53–58CrossRefPubMedGoogle Scholar
  15. Faiyaz-Ul-Haque M, Zaidi S, Al-Mureikhi M, Peltekova I, Tsui L, Teebi A (2007) Mutations in the CHX10 gene in non-syndromic microphthalmia/anophthalmia patients from Qatar. Clin Genet 72:164–166CrossRefPubMedGoogle Scholar
  16. Fantes J, Ragge N, Lynch S, McGill N, Collin J, Howard-Peebles P, Hayward C, Vivian A, Williamson K, van Heyningen V, FitzPatrick D (2003) Mutations in SOX2 cause anophthalmia. Nat Genet 33:461–463CrossRefPubMedGoogle Scholar
  17. Ferda Percin E, Ploder L, Yu J, Arici K, Horsford D, Rutherford A, Bapat B, Cox D, Duncan A, Kalnins V, Kocak-Altintas A, Sowden J, Traboulsi E, Sarfarazi M, McInnes R (2000) Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Nat Genet 25:397–401CrossRefPubMedGoogle Scholar
  18. Green E, Stubbs J, Levine E (2003) Genetic rescue of cell number in a mouse model of microphthalmia: interactions between Chx10 and G1-phase cell cycle regulators. Development 130:539–552CrossRefPubMedGoogle Scholar
  19. Gudbjartsson D, Jonasson K, Frigge M, Kong A (2000) Allegro, a new computer program for multipoint linkage analysis. Nat Genet 25:12–13CrossRefPubMedGoogle Scholar
  20. Héon E, Greenberg A, Kopp K, Rootman D, Vincent A, Billingsley G, Priston M, Dorval K, Chow R, McInnes R, Heathcote G, Westall C, Sutphin J, Semina E, Bremner R, Stone E (2002) VSX1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet 11:1029–1036CrossRefPubMedGoogle Scholar
  21. Hornby S, Xiao Y, Gilbert C, Foster A, Wang X, Liang X, Jing H, Wang L, Min W, Shi Y, Li Y (1999) Causes of childhood blindness in the People’s Republic of China: results from 1131 blind school students in 18 provinces. Br J Ophthalmol 83:929–932CrossRefPubMedGoogle Scholar
  22. Horsford D, Nguyen M, Sellar G, Kothary R, Arnheiter H, McInnes R (2005) Chx10 repression of Mitf is required for the maintenance of mammalian neuroretinal identity. Development 132:177–187CrossRefPubMedGoogle Scholar
  23. Iseri S, Osborne R, Farrall M, Wyatt A, Mirza G, Nürnberg G, Kluck C, Herbert H, Martin A, Hussain M, Collin J, Lathrop M, Nürnberg P, Ragoussis J, Ragge N (2009) Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies. Hum Mutat 30:1378–1386CrossRefPubMedGoogle Scholar
  24. Liew M, Pryor R, Palais R, Meadows C, Erali M, Lyon E, Wittwer C (2004) Genotyping of single-nucleotide polymorphisms by high-resolution melting of small amplicons. Clin Chem 50:1156–1164CrossRefPubMedGoogle Scholar
  25. Liu I, Chen J, Ploder L, Vidgen D, van der Kooy D, Kalnins V, McInnes R (1994) Developmental expression of a novel murine homeobox gene (Chx10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 13:377–393CrossRefPubMedGoogle Scholar
  26. Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick D, Nürnberg G, Brasch F, Schirmer-Zimmermann H, Tolmie J, Chitayat D, Houge G, Fernández-Martínez L, Keating S, Mortier G, Hennekam R, von der Wense A, Slavotinek A, Meinecke P, Bitoun P, Becker C, Nürnberg P, Reis A, Rauch A (2007) Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet 80:550–560CrossRefPubMedGoogle Scholar
  27. Ragge N, Brown A, Poloschek C, Lorenz B, Henderson R, Clarke M, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera J, Ruddle P, Hurst J, Collin J, Salt A, Cooper S, Thompson P, Sisodiya S, Williamson K, Fitzpatrick D, van Heyningen V, Hanson I (2005a) Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet 76:1008–1022CrossRefPubMedGoogle Scholar
  28. Ragge NK, Lorenz B, Schneider A, Bushby K, de Sanctis L, de Sanctis U, Salt A, Collin JR, Vivian AJ, Free SL, Thompson P, Williamson KA, Sisodiya SM, van Heyningen V, Fitzpatrick DR (2005b) SOX2 anophthalmia syndrome. Am J Med Genet A 135:1–7 discussion 8PubMedGoogle Scholar
  29. Reed G, Kent J, Wittwer C (2007) High-resolution DNA melting analysis for simple and efficient molecular diagnostics. Pharmacogenomics 8:597–608CrossRefPubMedGoogle Scholar
  30. Rowan S, Cepko C (2004) Genetic analysis of the homeodomain transcription factor Chx10 in the retina using a novel multifunctional BAC transgenic mouse reporter. Dev Biol 271:388–402CrossRefPubMedGoogle Scholar
  31. Rowan S, Cepko C (2005) A POU factor binding site upstream of the Chx10 homeobox gene is required for Chx10 expression in subsets of retinal progenitor cells and bipolar cells. Dev Biol 281:240–255CrossRefPubMedGoogle Scholar
  32. Rowan S, Chen C, Young T, Fisher D, Cepko C (2004) Transdifferentiation of the retina into pigmented cells in ocular retardation mice defines a new function of the homeodomain gene Chx10. Development 131:5139–5152CrossRefPubMedGoogle Scholar
  33. Semina E, Brownell I, Mintz-Hittner H, Murray J, Jamrich M (2001) Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet 10:231–236CrossRefPubMedGoogle Scholar
  34. Takano E, Mitchell G, Fox S, Dobrovic A (2008) Rapid detection of carriers with BRCA1 and BRCA2 mutations using high resolution melting analysis. BMC Cancer 8:59CrossRefPubMedGoogle Scholar
  35. Thiele H, Nürnberg P (2005) HaploPainter: a tool for drawing pedigrees with complex haplotypes. Bioinformatics 21:1730–1732CrossRefPubMedGoogle Scholar
  36. Tucker S, Jones B, Collin R (1996) Systemic anomalies in 77 patients with congenital anophthalmos or microphthalmos. Eye (Lond) 10(Pt 3):310–314Google Scholar
  37. Valleix S, Niel F, Nedelec B, Algros M, Schwartz C, Delbosc B, Delpech M, Kantelip B (2006) Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans. Am J Hum Genet 79:358–364CrossRefPubMedGoogle Scholar
  38. Vissers L, van Ravenswaaij C, Admiraal R, Hurst J, de Vries B, Janssen I, van der Vliet W, Huys E, de Jong P, Hamel B, Schoenmakers E, Brunner H, Veltman J, van Kessel A (2004) Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36:955–957CrossRefPubMedGoogle Scholar
  39. Voronina V, Kozhemyakina E, O’Kernick C, Kahn N, Wenger S, Linberg J, Schneider A, Mathers P (2004) Mutations in the human RAX homeobox gene in a patient with anophthalmia and sclerocornea. Hum Mol Genet 13:315–322CrossRefPubMedGoogle Scholar
  40. Wyatt A, Bakrania P, Bunyan D, Osborne R, Crolla J, Salt A, Ayuso C, Newbury-Ecob R, Abou-Rayyah Y, Collin J, Robinson D, Ragge N (2008) Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma. Hum Mutat 29:E278–E283CrossRefPubMedGoogle Scholar
  41. Yun S, Saijoh Y, Hirokawa KE, Kopinke D, Murtaugh LC, Monuki ES, Levine EM (2009) Lhx2 links the intrinsic and extrinsic factors that control optic cup formation. Development 136:3895–3906CrossRefPubMedGoogle Scholar
  42. Zenteno J, Perez-Cano H, Aguinaga M (2006) Anophthalmia-esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes. Am J Med Genet A 140:1899–1903PubMedGoogle Scholar
  43. Zhou J, Kherani F, Bardakjian T, Katowitz J, Hughes N, Schimmenti L, Schneider A, Young T (2008) Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia. Mol Vis 14:583–592PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Sibel Ugur Iseri
    • 1
  • Alexander W. Wyatt
    • 1
  • Gudrun Nürnberg
    • 2
    • 3
    • 4
  • Christian Kluck
    • 2
  • Peter Nürnberg
    • 2
    • 3
    • 4
  • Graham E. Holder
    • 5
  • Ed Blair
    • 6
  • Alison Salt
    • 7
    • 8
  • Nicola K. Ragge
    • 1
    • 9
    • 10
  1. 1.Department of Physiology, Anatomy, and GeneticsUniversity of OxfordOxfordUK
  2. 2.Cologne Center for GenomicsUniversity of CologneCologneGermany
  3. 3.Center for Molecular Medicine CologneUniversity of CologneCologneGermany
  4. 4.Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)University of CologneCologneGermany
  5. 5.Department of ElectrophysiologyMoorfields Eye HospitalLondonUK
  6. 6.Department of Clinical GeneticsOxford Radcliffe HospitalsOxfordUK
  7. 7.Department of PaediatricsMoorfields Eye HospitalLondonUK
  8. 8.Wolfson Neurodisability ServiceGreat Ormond St HospitalLondonUK
  9. 9.Department of Adnexal SurgeryMoorfields Eye HospitalLondonUK
  10. 10.Department of OphthalmologyBirmingham Children’s HospitalBirminghamUK

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