Abstract
Disorders of the anterior segment of the eye encompass a variety of clinical presentations including aniridia, Axenfeld and Rieger anomalies, primary congenital glaucoma, Peters anomaly, as well as syndromal associations. These conditions have a significant impact on vision due to disruption of the visual axis, and also secondary glaucoma which occurs in over 50% of patients. Ocular anterior segment disorders occur due to a complex interplay of developmental, embryological and genetic factors, and often have phenotypic overlaps and genetic heterogeneity. Here we present a review of the clinical features and genes associated with aniridia, Axenfeld and Rieger anomalies, primary congenital glaucoma, Peters anomaly, and syndromic forms of these conditions. We also highlight phenotype–genotype correlations, recent discoveries with next-generation sequencing which broaden known phenotypes, and new anterior segment genes and pathways. We provide a guide towards genetic diagnosis for clinicians investigating patients with anterior segment dysgenesis.
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References
Aalfs CM, Fantes JA, Wenniger-Prick LJ, Sluijter S, Hennekam RC, van Heyningen V, Hoovers JM (1997) Tandem duplication of 11p12-p13 in a child with borderline development delay and eye abnormalities: dose effect of the PAX6 gene product? Am J Med Genet 73:267–271
Acharya M et al (2006) Primary role of CYP1B1 in Indian juvenile-onset POAG patients molecular vision 12:399–404
Ali M et al (2009) Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 84:664–671. https://doi.org/10.1016/j.ajhg.2009.03.017
Aliferis K et al (2010) A novel nonsense B3GALTL mutation confirms Peters plus syndrome in a patient with multiple malformations and Peters anomaly. Ophthalmic Genet 31:205–208. https://doi.org/10.3109/13816810.2010.512355
Alsaif HS et al (2018) Congenital glaucoma and CYP1B1: an old story revisited. Hum Genet. https://doi.org/10.1007/s00439-018-1878-z
Alward WL (2000) Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 130:107–115
Anand D, Agrawal SA, Slavotinek A, Lachke SA (2018) Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects. Hum Mutat 39:471–494. https://doi.org/10.1002/humu.23395
Azmanov DN et al (2011) LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population Eur. J Hum Genet 19:326–333. https://doi.org/10.1038/ejhg.2010.181
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, Yamaguchi Y, Handa H, Hayakawa M, Kanai A, Yamada M (1999) Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies. Am J Hum Genet 65:656–663. https://doi.org/10.1086/302529
Banerjee A, Chakraborty S, Chakraborty A, Chakrabarti S, Ray K (2016) Functional and structural analyses of CYP1B1 variants linked to congenital and adult-onset glaucoma to investigate the molecular basis of these diseases. PloS One 11:e0156252 https://doi.org/10.1371/journal.pone.0156252
Beebe DC, Coats JM (2000) The lens organizes the anterior segment: specification of neural crest cell differentiation in the avian eye. Dev Biol 220:424–431. https://doi.org/10.1006/dbio.2000.9638
Bejjani BA et al (1998) Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet 62:325–333. https://doi.org/10.1086/301725
Berry V et al (2004) Recurrent 17 bp duplication in PITX3 is primarily associated with posterior polar cataract (CPP4). J Med Genet 41:e109. https://doi.org/10.1136/jmg.2004.020289
Berry FB, Lines MA, Oas JM, Footz T, Underhill DA, Gage PJ, Walter MA (2006) Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Mol Genet 15:905–919. https://doi.org/10.1093/hmg/ddl008
Beyer EC, Ebihara L, Berthoud VM (2013) Connexin mutants and cataracts. Front Pharmacol 4:43. https://doi.org/10.3389/fphar.2013.00043
Bhandari R, Ferri S, Whittaker B, Liu M, Lazzaro DR (2011) Peters anomaly: review of the literature. Cornea 30:939–944. https://doi.org/10.1097/ICO.0b013e31820156a9
Blixt A, Mahlapuu M, Aitola M, Pelto-Huikko M, Enerback S, Carlsson P (2000) A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev 14:245–254
Ceroni F et al (2018) New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies. Hum Genet. https://doi.org/10.1007/s00439-018-1875-2
Chakrabarti S, Kaur K, Rao KN, Mandal AK, Kaur I, Parikh RS, Thomas R (2009) The transcription factor gene FOXC1 exhibits a limited role in primary congenital glaucoma Invest. Ophthalmol Vis Sci 50:75–83. https://doi.org/10.1167/iovs.08-2253
Chang T, Brookes J, Carvuoto K, Bitrian E, Grajewski A (2013) Primary congenital glaucoma and Juvenile open-angle glaucoma. Amsterdam
Chauhan BK, Yang Y, Cveklova K, Cvekl A (2004) Functional properties of natural human PAX6 and PAX6(5a)mutants. Invest Ophthalmol Vis Sci 45:385–392
Chavarria-Soley G, Michels-Rautenstrauss K, Caliebe A, Kautza M, Mardin C, Rautenstrauss B (2006) Novel CYP1B1 and known PAX6 mutations in anterior segment dysgenesis (ASD). J Glaucoma 15:499–504. https://doi.org/10.1097/01.ijg.0000243467.28590.6a
Chen L, Gage PJ (2016) Heterozygous Pitx2 null mice accurately recapitulate the ocular features of Axenfeld-Rieger syndrome and congenital glaucoma invest. Ophthalmol Vis Sci 57:5023–5030. https://doi.org/10.1167/iovs.16-19700
Cheong SS et al (2016) Mutations in CPAMD8 cause a unique form of autosomal-recessive anterior segment dysgenesis. Am J Hum Genet 99:1338–1352. https://doi.org/10.1016/j.ajhg.2016.09.022
Chouiter L, Nadifi S (2017) Analysis of CYP1B1 gene mutations in patients with primary congenital glaucoma. J Pediatr Genet 6:205–214. https://doi.org/10.1055/s-0037-1602695
Chudasama KK et al (2013) SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet 93:150–157. https://doi.org/10.1016/j.ajhg.2013.05.023
Churchill A, Booth A (1996) Genetics of aniridia and anterior segment dysgenesis. Br J Ophthalmol 80:669–673
Cox CJ et al (2002) Differential regulation of gene expression by PITX2 isoforms. J Biol Chem 277:25001–25010. https://doi.org/10.1074/jbc.M201737200
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. https://doi.org/10.1086/344396
D’Haene B et al (2011) Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations. Invest Ophthalmol Vis Sci 52:324–333. https://doi.org/10.1167/iovs.10-5309
Dassie-Ajdid J et al (2009) Novel B3GALTL mutation in Peters-plus. Syndrome Clin Genet 76:490–492. https://doi.org/10.1111/j.1399-0004.2009.01253.x
Davis JA, Reed RR (1996) Role of Olf-1 and Pax-6 transcription factors in neurodevelopment. J Neurosci 16:5082–5094
Davis-Silberman N, Ashery-Padan R (2008) Iris development in vertebrates; genetic and molecular considerations. Brain Res 1192:17–28
Desir J, Sznajer Y, Depasse F, Roulez F, Schrooyen M, Meire F, Abramowicz M (2010) LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma. Eur J Hum Genet: EJHG 18:761–767. https://doi.org/10.1038/ejhg.2010.11
Du RF, Huang H, Fan LL, Li XP, Xia K, Xiang R (2016) A novel mutation of FOXC1 (R127L) in an Axenfeld-Rieger syndrome family with glaucoma and multiple congenital heart. Dis Ophthalmic Genet 37:111–115. https://doi.org/10.3109/13816810.2014.924016
Dyment DA et al (2013) Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet 93:158–166. https://doi.org/10.1016/j.ajhg.2013.06.005
Edward D, Al Rajhi A, Lewis RA, Curry S, Wang Z, Bejjani B (2004) Molecular basis of Peters anomaly in Saudi. Arabia Ophthalmic Genet 25:257–270. https://doi.org/10.1080/13816810490902648
El-Koofy NM, El-Mahdy R, Fahmy ME, El-Hennawy A, Farag MY, El-Karaksy HM (2011) Alagille syndrome: clinical and ocular pathognomonic features. Eur J Ophthalmol 21:199–206
Elliott JH, Feman SS, O’Day DM, Garber M (1985) Hereditary sclerocornea. Arch Ophthalmol 103:676–679
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. https://doi.org/10.1111/j.1460-9568.2004.03236.x
Epstein JA, Glaser T, Cai J, Jepeal L, Walton DS, Maas RL (1994) Two independent and interactive DNA-binding subdomains of the Pax6 paired domain are regulated by alternative splicing. Genes Dev 8:2022–2034
Erickson RP (2001) Forkhead genes and human disease. J Appl Genet 42:211–221
Fantes JA, Bickmore WA, Fletcher JM, Ballesta F, Hanson IM, van Heyningen V (1992) Submicroscopic deletions at the WAGR locus revealed by nonradioactive in situ hybridization. Am J Hum Genet 51:1286–1294
Gage PJ, Suh H, Camper SA (1999) Dosage requirement of Pitx2 for development of multiple organs. Development 126:4643–4651
Gage PJ, Rhoades W, Prucka SK, Hjalt T (2005) Fate maps of neural crest and mesoderm in the mammalian eye Invest. Ophthalmol Vis Sci 46:4200–4208. https://doi.org/10.1167/iovs.05-0691
Glaser T, Walton DS, Maas RL (1992) Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet 2:232–239. https://doi.org/10.1038/ng1192-232
Glaser T, Jepeal L, Edwards JG, Young SR, Favor J, Maas RL (1994) PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 7:463–471. https://doi.org/10.1038/ng0894-463
Gorlin RJ, Cervenka J, Moller K, Horrobin M, Witkop CJ Jr (1975) Malformation syndromes. A selected miscellany. Birth Defects Orig Artic Ser 11:39–50
Graw J (2003) The genetic and molecular basis of congenital eye defects. Nat Rev Genet 4:876–888. https://doi.org/10.1038/nrg1202
Gripp KW, Hopkins E, Jenny K, Thacker D, Salvin J (2013) Cardiac anomalies in Axenfeld-Rieger syndrome due to a novel FOXC1 mutation. Am J Med Genet A 161A:114–119. https://doi.org/10.1002/ajmg.a.35697
Gronskov K et al (2001) Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet 109:11–18
Gudbjartsson DF et al (2007) Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448:353–357. https://doi.org/10.1038/nature06007
Haji-Seyed-Javadi R et al (2012) LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat 33:1182–1187. https://doi.org/10.1002/humu.22105
Halder G, Callaerts P, Gehring WJ (1995) New perspectives on eye evolution. Curr Opin Genet Dev 5:602–609
Hanson IM et al (1994) Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet 6:168–173. https://doi.org/10.1038/ng0294-168
Harendza S et al (2005) Renal failure and hypertension in Alagille syndrome with a novel JAG1 mutation. J Nephrol 18:312–317
Hill RE et al (1991) Mouse small eye results from mutations in a paired-like homeobox containing gene. Nature 354:522–525. https://doi.org/10.1038/354522a0
Hingorani M et al (1999) Ocular abnormalities in Alagille syndrome. Ophthalmology 106:330–337. https://doi.org/10.1016/S0161-6420(99)90072-6
Hingorani M, Williamson KA, Moore AT, van Heyningen V (2009) Detailed ophthalmologic evaluation of 43 individuals with PAX6 mutations. Invest Ophthalmol Vis Sci 50:2581–2590. https://doi.org/10.1167/iovs.08-2827
Ho HY, Chang KH, Nichols J, Li M (2009) Homeodomain protein Pitx3 maintains the mitotic activity of lens epithelial cells. Mech Dev 126:18–29. https://doi.org/10.1016/j.mod.2008.10.007
Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT (2006) A review of anterior segment dysgeneses. Surv Ophthalmol 51:213–231
Inoue T et al (2014) Latent TGF-beta binding protein-2 is essential for the development of ciliary zonule microfibrils. Hum Mol Genet 23:5672–5682. https://doi.org/10.1093/hmg/ddu283
Iseri SU et al (2009) Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies. Hum Mutat 30:1378–1386. https://doi.org/10.1002/humu.21079
Islam L, Kelberman D, Williamson L, Lewis N, Glindzicz MB, Nischal KK, Sowden JC (2015) Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease. Hum Mutat 36:296–300. https://doi.org/10.1002/humu.22741
Jamieson RV, Grigg JR (2013) Clinical embryology and development of the eye. In: Hoyt CS, Taylor D (eds) Pediatric ophthalmology and strabismus, 4th edn. Saunders/Elsevier, Edinburgh, pp 9–16
Jamieson RV et al (2002) Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma. Hum Mol Genet 11:33–42
Kamath BM et al (2012) NOTCH2 mutations in Alagille syndrome. J Med Genet 49:138–144. https://doi.org/10.1136/jmedgenet-2011-100544
Khalil A et al (2017) A novel mutation in FOXC1 in a lebanese family with congenital heart disease and anterior Segment dysgenesis: potential roles for NFATC1 and DPT in the phenotypic variations. Front Cardiovasc Med 4:58. https://doi.org/10.3389/fcvm.2017.00058
Khan K et al (2011) Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma Am. J Hum Genet 89:464–473. https://doi.org/10.1016/j.ajhg.2011.08.005
Khan SY et al (2016) FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nat Commun 7:10953. https://doi.org/10.1038/ncomms10953
Kuang SQ et al (2016) FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest 126:948–961. https://doi.org/10.1172/JCI83778
Kumar A, Duvvari MR, Prabhakaran VC, Shetty JS, Murthy GJ, Blanton SH (2010) A homozygous mutation in LTBP2 causes isolated microspherophakia. Hum Genet 128:365–371. https://doi.org/10.1007/s00439-010-0858-8
Lesnik Oberstein SA et al (2006) Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase American. J Hum Genet 79:562–566. https://doi.org/10.1086/507567
Li ZF, Wu XH, Engvall E (2004) Identification and characterization of CPAMD8, a novel member of the complement 3/alpha2-macroglobulin family with a C-terminal Kazal domain. Genomics 83:1083–1093. https://doi.org/10.1016/j.ygeno.2003.12.005
Li N, Zhou Y, Du L, Wei M, Chen X (2011) Overview of Cytochrome P450 1B1 gene mutations in patients with primary congenital glaucoma. Experimental eye research 93:572–579. https://doi.org/10.1016/j.exer.2011.07.009
Limaye N et al (2009) Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet 41:118–124. https://doi.org/10.1038/ng.272
Lin CR et al (1999) Pitx2 regulates lung asymmetry cardiac positioning pituitary tooth morphogenesis. Nature 401:279–282. https://doi.org/10.1038/45803
Lines MA, Kozlowski K, Walter MA (2002) Molecular genetics of Axenfeld-Rieger malformations. Hum Mol Genet 11:1177–1184
Liu H et al (2017) Whole exome sequencing identifies a novel mutation in the PITX3 gene, causing autosomal dominant congenital cataracts in a Chinese family. Ann Clin Lab Sci 47:92–95
Lopez-Garrido MP, Sanchez-Sanchez F, Lopez-Martinez F, Aroca-Aguilar JD, Blanco-Marchite C, Coca-Prados M, Escribano J (2006) Heterozygous CYP1B1 gene mutations in Spanish patients with primary open-angle glaucoma. Mol Vis 12:748–755
Lubitz SA et al (2014) Novel genetic markers associate with atrial fibrillation risk in Europeans and. Jpn J Am Coll Cardiol 63:1200–1210. https://doi.org/10.1016/j.jacc.2013.12.015
Ma AS, Grigg JR, Prokudin I, Flaherty M, Bennetts B, Jamieson RV (2018) New mutations in GJA8 expand the phenotype to include total sclerocornea. Clin Genet 93:155–159. https://doi.org/10.1111/cge.13045
Makino S, Ohkubo Y, Tampo H (2012) Optical coherence tomography and fundus autofluorescence imaging study of chorioretinal atrophy involving the macula in Alagille syndrome. Clin Ophthalmol 6:1445–1448. https://doi.org/10.2147/OPTH.S36146
Mao M, Kiss M, Ou Y, Gould DB (2017) Genetic dissection of anterior segment dysgenesis caused by a Col4a1 mutation in mouse. Dis Model Mech 10:475–485. https://doi.org/10.1242/dmm.027888
Mathias RT, White TW, Gong X (2010) Lens gap junctions in growth, differentiation, and homeostasis. Physiol Rev 90:179–206. https://doi.org/10.1152/physrev.00034.2009
Matsubara A, Ozeki H, Matsunaga N, Nozaki M, Ashikari M, Shirai S, Ogura Y (2001) Histopathological examination of two cases of anterior staphyloma associated with Peters’ anomaly and persistent hyperplastic primary vitreous. Br J Ophthalmol 85:1421–1425
McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79:169–173. https://doi.org/10.1086/505332
McMenamin PG (1991) A quantitative study of the prenatal development of the aqueous outflow system in the human eye. Exp Eye Res 53:507–517
Medina-Martinez O, Shah R, Jamrich M (2009) Pitx3 controls multiple aspects of lens development. Dev Dyn 238:2193–2201. https://doi.org/10.1002/dvdy.21924
Medina-Trillo C, Aroca-Aguilar JD, Mendez-Hernandez CD, Morales L, Garcia-Anton M, Garcia-Feijoo J, Escribano J (2016) Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences. Eur J Hum Genet 24:672–680. https://doi.org/10.1038/ejhg.2015.169
Melki R, Colomb E, Lefort N, Brezin AP, Garchon HJ (2004) CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma. J Med Genet 41:647–651. https://doi.org/10.1136/jmg.2004.020024
Meuwissen ME et al (2015) The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med 17:843–853. https://doi.org/10.1038/gim.2014.210
Narooie-Nejad M et al (2009) Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Hum Mol Genet 18:3969–3977. https://doi.org/10.1093/hmg/ddp338
Nelson LB, Spaeth GL, Nowinski TS, Margo CE, Jackson L (1984) Aniridia. A review. Surv Ophthalmol 28:621–642
Nischal KK (2007) Congenital corneal opacities—a surgical approach to nomenclature and classification. Eye (Lond) 21:1326–1337. https://doi.org/10.1038/sj.eye.6702840
Nischal KK, Sowden JC (2013) Anterior segment: developmental anomalies. In: Hoyt CS, Taylor D (eds) Pediatric ophthalmology and strabismus, 4th edn. Saunders/Elsevier, Edinburgh
Nishimura DY et al (1998) The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet 19:140–147. https://doi.org/10.1038/493
Nishimura DY et al (2001) A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye Am. J Hum Genet 68:364–372. https://doi.org/10.1086/318183
Ormestad M, Blixt A, Churchill A, Martinsson T, Enerback S, Carlsson P (2002) Foxe3 haploinsufficiency in mice: a model for Peters’ anomaly Invest. Ophthalmol Vis Sci 43:1350–1357
Partanen J et al (1992) A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol 12:1698–1707
Philippakis AA et al (2015) The Matchmaker Exchange: a platform for rare disease gene discovery. Hum Mutat 36:915–921. https://doi.org/10.1002/humu.22858
Plaisancie J et al (2017) FOXE3 mutations: genotype-phenotype correlations Clin Genet https://doi.org/10.1111/cge.13177
Prosser J, van Heyningen V (1998) PAX6 mutations reviewed Hum Mutat 11:93–108. https://doi.org/10.1002/(SICI)1098-1004(1998)11:2%3C93::AID-HUMU1%3E3.0.CO;2-M
Reis LM, Semina EV (2011) Genetics of anterior segment dysgenesis disorders. Curr Opin Ophthalmol 22:314–324. https://doi.org/10.1097/ICU.0b013e328349412b
Reis LM, Tyler RC, Schneider A, Bardakjian T, Stoler JM, Melancon SB, Semina EV (2010) FOXE3 plays a significant role in autosomal recessive microphthalmia. Am J Med Genet Part A 152A:582–590 https://doi.org/10.1002/ajmg.a.33257
Reis LM et al (2012) PITX2 and FOXC1 spectrum of mutations in ocular syndromes. Eur J Hum Genet 20:1224–1233. https://doi.org/10.1038/ejhg.2012.80
Robinson DO, Howarth RJ, Williamson KA, van Heyningen V, Beal SJ, Crolla JA (2008) Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia. Am J Med Genet A 146A:558–569. https://doi.org/10.1002/ajmg.a.32209
Rosemann M et al (2010) Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 (416insG) mice. Mamm Genome 21:13–27. https://doi.org/10.1007/s00335-009-9235-0
Schroeder C et al (2014) PIK3R1 mutations in SHORT syndrome. Clin Genet 86:292–294. https://doi.org/10.1111/cge.12263
Semina EV et al (1996) Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392–399. https://doi.org/10.1038/ng1296-392
Semina EV, Reiter RS, Murray JC (1997) Isolation of a new homeobox gene belonging to the Pitx/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum Mol Genet 6:2109–2116
Semina EV et al (1998) A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and. ASMD Nat Genet 19:167–170. https://doi.org/10.1038/527
Semina EV, Murray JC, Reiter R, Hrstka RF, Graw J (2000) Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice. Hum Mol Genet 9:1575–1585
Semina EV, Brownell I, Mintz-Hittner HA, Murray JC, 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
Seo S, Kume T (2006) Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract. Dev Biol 296:421–436. https://doi.org/10.1016/j.ydbio.2006.06.012
Shi Y, Tu Y, De Maria A, Mecham RP, Bassnett S (2013) Development, composition, and structural arrangements of the ciliary zonule of the mouse. Investig Ophthalmol Vis Sci 54:2504–2515. https://doi.org/10.1167/iovs.13-11619
Sisodiya SM et al (2001) PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nat Genet 28:214–216. https://doi.org/10.1038/90042
Smith RS et al (2000) Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet 9:1021–1032
Souma T et al (2016) Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J Clin Invest 126:2575–2587. https://doi.org/10.1172/JCI85830
Sowden JC (2007) Molecular and developmental mechanisms of anterior segment dysgenesis. Eye (Lond) 21:1310–1318. https://doi.org/10.1038/sj.eye.6702852
Spencer WH (ed) (1996) Ophthalmic pathology: an atlas and textbook, vol 1, 4th edn. W.B. Saunders Company, Philadelphia
Stoilov I, Akarsu AN, Sarfarazi M (1997) Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet 6:641–647
Stone DL, Kenyon KR, Green WR, Ryan SJ (1976) Congenital central corneal leukoma (Peters’ anomaly). Am J Ophthalmol 81:173–193
Strungaru MH, Dinu I, Walter MA (2007) Genotype-phenotype correlations in Axenfeld-Rieger malformation and glaucoma patients with FOXC1 and PITX2 mutations Invest. Ophthalmol Vis Sci 48:228–237. https://doi.org/10.1167/iovs.06-0472
Summers KM, Withers SJ, Gole GA, Piras S, Taylor PJ (2008) Anterior segment mesenchymal dysgenesis in a large Australian family is associated with the recurrent 17 bp duplication in PITX3. Mol Vis 14:2010–2015
Sun YM et al (2016) PITX2 loss-of-function mutation contributes to tetralogy of. Fallot Gene 577:258–264. https://doi.org/10.1016/j.gene.2015.12.001
Tamura K, Yonei-Tamura S, Izpisua Belmonte JC (1999) Molecular basis of left-right asymmetry. Dev Growth Differ 41:645–656
Tanwar M, Dada T, Dada R (2010) Axenfeld-Rieger syndrome associated with congenital glaucoma and cytochrome P4501B1 gene mutations. Case Rep Med. https://doi.org/10.1155/2010/212656
Thomson BR et al (2017) Angiopoietin-1 is required for Schlemm’s canal development in mice and humans. J Clin Invest. https://doi.org/10.1172/JCI95545
Tumer Z, Bach-Holm D (2009) Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations Eur. J Hum Genet 17:1527–1539. https://doi.org/10.1038/ejhg.2009.93
Tzoulaki I, White IM, Hanson IM (2005) PAX6 mutations: genotype-phenotype correlations. BMC Genet 6:27. https://doi.org/10.1186/1471-2156-6-27
Valenzuela A, Cline RA (2004) Ocular and nonocular findings in patients with aniridia. Can J Ophthalmol 39:632–638
van Heyningen V, Williamson KA (2002) PAX6 in sensory development. Hum Mol Genet 11:1161–1167
Verdin H, Sorokina EA, Meire F, Casteels I, de Ravel T, Semina EV, De Baere E (2014) Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics. Orphanet J Rare Dis 9:26. https://doi.org/10.1186/1750-1172-9-26
Vincent A et al (2001) Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters’ anomaly. J Med Genet 38:324–326
Vincent AL et al (2002) Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 70:448–460. https://doi.org/10.1086/338709
Vincent MC, Pujo AL, Olivier D, Calvas P (2003) Screening for PAX6 gene mutations is consistent with haploinsufficiency as the main mechanism leading to various ocular defects. Eur J Hum Genet 11:163–169. https://doi.org/10.1038/sj.ejhg.5200940
Wada K et al (2014) Expression of truncated PITX3 in the developing lens leads to microphthalmia and aphakia in mice. PLoS One 9:e111432. https://doi.org/10.1371/journal.pone.0111432
Walther C, Gruss P (1991) Pax-6, a murine paired box gene, is expressed in the developing. CNS Dev 113:1435–1449
Warthen DM et al (2006) Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat 27:436–443. https://doi.org/10.1002/humu.20310
Weh E et al (2014) Whole exome sequence analysis of Peters anomaly. Hum Genet 133:1497–1511. https://doi.org/10.1007/s00439-014-1481-x
Xu W, Rould MA, Jun S, Desplan C, Pabo CO (1995) Crystal structure of a paired domain-DNA complex at 2.5 A resolution reveals structural basis for Pax developmental mutations. Cell 80:639–650
Zhang X et al (2015) Variants in TRIM44 Cause Aniridia by Impairing PAX6 expression. Hum Mutat 36:1164–1167. https://doi.org/10.1002/humu.22907
Acknowledgements
RVJ and JRG acknowledge support from NHMRC grant APP1116360, the NSW Office of Health and Medical Research, Costco, the Sydney Research Excellence Initiative and the Ophthalmic Research Institute of Australia.
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Ma, A.S., Grigg, J.R. & Jamieson, R.V. Phenotype–genotype correlations and emerging pathways in ocular anterior segment dysgenesis. Hum Genet 138, 899–915 (2019). https://doi.org/10.1007/s00439-018-1935-7
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DOI: https://doi.org/10.1007/s00439-018-1935-7