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.
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References
Abecasis G, Cherny S, Cookson W, Cardon L (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101
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 37:221–223
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 91:1471–1476
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 82:304–319
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 63:133–143
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 115:302–309
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 62:1113–1116
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 94:386–388
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 12:376–384
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 7:21–28
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 109:315–322
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 1192:99–113
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 47:386–396
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 34:53–58
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 72:164–166
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 33:461–463
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 25:397–401
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 130:539–552
Gudbjartsson D, Jonasson K, Frigge M, Kong A (2000) Allegro, a new computer program for multipoint linkage analysis. Nat Genet 25:12–13
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 11:1029–1036
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 83:929–932
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 132:177–187
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 30:1378–1386
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 50:1156–1164
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 13:377–393
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 80:550–560
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 76:1008–1022
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 8
Reed G, Kent J, Wittwer C (2007) High-resolution DNA melting analysis for simple and efficient molecular diagnostics. Pharmacogenomics 8:597–608
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 271:388–402
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 281:240–255
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 131:5139–5152
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 10:231–236
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 8:59
Thiele H, Nürnberg P (2005) HaploPainter: a tool for drawing pedigrees with complex haplotypes. Bioinformatics 21:1730–1732
Tucker S, Jones B, Collin R (1996) Systemic anomalies in 77 patients with congenital anophthalmos or microphthalmos. Eye (Lond) 10(Pt 3):310–314
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 79:358–364
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 36:955–957
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 13:315–322
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–E283
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 136:3895–3906
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 140:1899–1903
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 14:583–592
Acknowledgments
We thank the affected individuals and their families for their enthusiastic participation in this study. We are grateful to Dr Angela Martin for research co-ordination and all the referring clinicians, in particular Mr Nick George, Mr Richard Markham and Dr Rania El Essawy. N.R. is a Senior Surgical Scientist supported by the Academy of Medical Sciences/The Health Foundation. We gratefully acknowledge the generous support by grants from Newlife (SUI), VICTA (Visually Impaired Children Taking Action), late Henri Ernest Polak Trust (AW), MACS (Microphthalmia, Anophthalmia Children’s Society) and the National Institute for Health Research UK (Moorfields Eye Hospital Biomedical Research Centre; GEH).
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Iseri, S.U., Wyatt, A.W., Nürnberg, G. et al. 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. Hum Genet 128, 51–60 (2010). https://doi.org/10.1007/s00439-010-0823-6
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DOI: https://doi.org/10.1007/s00439-010-0823-6