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New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies

  • Fabiola Ceroni
  • Domingo Aguilera-Garcia
  • Nicolas Chassaing
  • Dorine Arjanne Bax
  • Fiona Blanco-Kelly
  • Patricia Ramos
  • Maria Tarilonte
  • Cristina Villaverde
  • Luciana Rodrigues Jacy da Silva
  • Maria Juliana Ballesta-Martínez
  • Maria Jose Sanchez-Soler
  • Richard James Holt
  • Lisa Cooper-Charles
  • Jonathan Bruty
  • Yvonne Wallis
  • Dominic McMullan
  • Jonathan Hoffman
  • David Bunyan
  • Alison Stewart
  • Helen Stewart
  • Katherine Lachlan
  • DDD Study
  • Alan Fryer
  • Victoria McKay
  • Joëlle Roume
  • Pascal Dureau
  • Anand Saggar
  • Michael Griffiths
  • Patrick Calvas
  • Carmen Ayuso
  • Marta Corton
  • Nicola K RaggeEmail author
Original Investigation
Part of the following topical collections:
  1. Eye Genetics

Abstract

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

Notes

Acknowledgements

We would like to thank the patients and their families for their participation in our study. We are grateful to Suzanne Broadgate for assisting with the coordination of the project. We thank the Centrum Menselijke Erfelijkheid laboratory, Leuven, Belgium, for the diagnostic PAX2 testing. We also thank Dr Jean-Philippe Bault for the ultrasound examinations performed on family 2. This work was supported by grants from Baillie Gifford, Visually Impaired Children Taking Action (VICTA) (http://www.victa.org.uk/), Microphthalmia, Anophthalmia, Coloboma Support (MACS) (http://www.macs.org.uk), Oxford Brookes University Central Research Fund, Retina France, Fondation Maladies Rares, Spanish Institute of Health Carlos III (CP12/03256), Spanish Ministry of Economy and Competitiveness (SAF2013–46943-R), Mutua Madrileña Foundation and Cátedra de Patrocinio UAM-IIS-FJD of Genomic Medicine (University Autónoma of Madrid). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], see http://www.ddduk.org/access.html for full acknowledgement.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

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References

  1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249CrossRefPubMedPubMedCentralGoogle Scholar
  2. Balikova I, de Ravel T, Ayuso C, Thienpont B, Casteels I, Villaverde C, Devriendt K, Fryns JP, Vermeesch JR (2011) High frequency of submicroscopic chromosomal deletions in patients with idiopathic congenital eye malformations. Am J Ophthalmol 151(6):1087–1094.e45Google Scholar
  3. Bernier R, Steinman KJ, Reilly B, Wallace AS, Sherr EH, Pojman N, Mefford HC, Gerdts J, Earl R, Hanson E et al (2016) Clinical phenotype of the recurrent 1q21.1 copy-number variant. Genet Med 18(4):341–349CrossRefPubMedGoogle Scholar
  4. Berthoud VM, Minogue PJ, Yu H, Schroeder R, Snabb JI, Beyer EC (2013) Connexin50D47A decreases levels of fiber cell connexins and impairs lens fiber cell differentiation. Invest Ophthalmol Vis Sci 54(12):7614–7622CrossRefPubMedPubMedCentralGoogle Scholar
  5. Beyer EC, Ebihara L, Berthoud VM (2013) Connexin mutants and cataracts. Front Pharmacol 4:43PubMedPubMedCentralGoogle Scholar
  6. Bienz M (2005) beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr Biol 15(2):R64–R67CrossRefPubMedGoogle Scholar
  7. Bower M, Salomon R, Allanson J, Antignac C, Benedicenti F, Benetti E, Binenbaum G, Jensen UB, Cochat P, DeCramer S et al (2012) Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum Mutat 33(3):457–466CrossRefPubMedGoogle Scholar
  8. Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M et al (2008) Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 40(12):1466–1471CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cantù C, Zimmerli D, Hausmann G, Valenta T, Moor A, Aguet M, Basler K (2014) Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development. Genes Dev 28(17):1879–1884CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chang B, Wang X, Hawes NL, Ojakian R, Davisson MT, Lo WK, Gong X (2002) A Gja8 (Cx50) point mutation causes an alteration of alpha 3 connexin (Cx46) in semi-dominant cataracts of Lop10 mice. Hum Mol Genet 11(5):507–513CrossRefPubMedGoogle Scholar
  11. Chassaing N, Ragge N, Plaisancié J, Patat O, Geneviève D, Rivier F, Malrieu-Eliaou C, Hamel C, Kaplan J, Calvas P (2016) Confirmation of TENM3 involvement in autosomal recessive colobomatous microphthalmia. Am J Med Genet A 170(7):1895–1898CrossRefPubMedGoogle Scholar
  12. Chung J, Berthoud VM, Novak L, Zoltoski R, Heilbrunn B, Minogue PJ, Liu X, Ebihara L, Kuszak J, Beyer EC (2007) Transgenic overexpression of connexin50 induces cataracts. Exp Eye Res 84(3):513–528CrossRefPubMedPubMedCentralGoogle Scholar
  13. Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S (2010) Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol 6(12):e1001025CrossRefPubMedPubMedCentralGoogle Scholar
  14. Devi RR, Vijayalakshmi P (2006) Novel mutations in GJA8 associated with autosomal dominant congenital cataract and microcornea. Mol Vis 12:190–195PubMedGoogle Scholar
  15. Fernandez-San Jose P, Corton M, Blanco-Kelly F, Avila-Fernandez A, Lopez-Martinez MA, Sanchez-Navarro I, Sanchez-Alcudia R, Perez-Carro R, Zurita O, Sanchez-Bolivar N et al (2015) Targeted next-generation sequencing improves the diagnosis of autosomal dominant retinitis pigmentosa in Spanish patients. Invest Ophthalmol Vis Sci 56(4):2173–2182CrossRefPubMedGoogle Scholar
  16. García IE, Prado P, Pupo A, Jara O, Rojas-Gómez D, Mujica P, Flores-Muñoz C, González-Casanova J, Soto-Riveros C, Pinto BI et al (2016) Connexinopathies: a structural and functional glimpse. BMC Cell Biol 17(Suppl 1):17CrossRefPubMedPubMedCentralGoogle Scholar
  17. Gillespie RL, O’Sullivan J, Ashworth J, Bhaskar S, Williams S, Biswas S, Kehdi E, Ramsden SC, Clayton-Smith J, Black GC et al (2014) Personalized diagnosis and management of congenital cataract by next-generation sequencing. Ophthalmology 121(11):2124–2137.e1-2Google Scholar
  18. Girirajan S, Eichler EE (2010) Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet 19(R2):R176–R187CrossRefPubMedPubMedCentralGoogle Scholar
  19. Gong X, Li E, Klier G, Huang Q, Wu Y, Lei H, Kumar NM, Horwitz J, Gilula NB (1997) Disruption of alpha3 connexin gene leads to proteolysis and cataractogenesis in mice. Cell 91(6):833–843CrossRefPubMedGoogle Scholar
  20. Graw J, Löster J, Soewarto D, Fuchs H, Meyer B, Reis A, Wolf E, Balling R, Hrabé de Angelis M (2001) Characterization of a mutation in the lens-specific MP70 encoding gene of the mouse leading to a dominant cataract. Exp Eye Res 73(6):867–876CrossRefPubMedGoogle Scholar
  21. Ha K, Shen Y, Graves T, Kim CH, Kim HG (2016) The presence of two rare genomic syndromes, 1q21 deletion and Xq28 duplication, segregating independently in a family with intellectual disability. Mol Cytogenet 9:74CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hansen L, Yao W, Eiberg H, Kjaer KW, Baggesen K, Hejtmancik JF, Rosenberg T (2007) Genetic heterogeneity in microcornea-cataract: five novel mutations in CRYAA, CRYGD, and GJA8. Invest Ophthalmol Vis Sci 48(9):3937–3944CrossRefPubMedGoogle Scholar
  23. Holt R, Ugur Iseri SA, Wyatt AW, Bax DA, Gold Diaz D, Santos C, Broadgate S, Dunn R, Bruty J, Wallis Y et al (2017) Identification and functional characterisation of genetic variants in OLFM2 in children with developmental eye disorders. Hum Genet 136(1):119–127CrossRefPubMedGoogle Scholar
  24. Hu S, Wang B, Zhou Z, Zhou G, Wang J, Ma X, Qi Y (2010) A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree. Mol Vis 16:1585–1592PubMedPubMedCentralGoogle Scholar
  25. Iseri SU, Osborne RJ, Farrall M, Wyatt AW, Mirza G, Nürnberg G, Kluck C, Herbert H, Martin A, Hussain MS et al (2009) Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies. Hum Mutat 30(10):1378–1386CrossRefPubMedGoogle Scholar
  26. Javadiyan S, Craig JE, Souzeau E, Sharma S, Lower KM, Mackey DA, Staffieri SE, Elder JE, Taranath D, Straga T et al (2017) High throughput genetic screening of 51 paediatric cataract genes identifies causative mutations in inherited paediatric cataract in South Eastern Australia. G3 (Bethesda) 7(10):3257–3268Google Scholar
  27. Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM et al (2007) Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet 80(2):232–240CrossRefPubMedGoogle Scholar
  28. Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(7):1073–1081CrossRefPubMedGoogle Scholar
  29. Kuo DS, Sokol JT, Minogue PJ, Berthoud VM, Slavotinek AM, Beyer EC, Gould DB (2017) Characterization of a variant of gap junction protein α8 identified in a family with hereditary cataract. PLoS ONE 12(8):e0183438CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291CrossRefPubMedPubMedCentralGoogle Scholar
  31. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25(14):1754–1760CrossRefPubMedPubMedCentralGoogle Scholar
  32. Liska F, Chylíková B, Martínek J, Kren V (2008) Microphthalmia and cataract in rats with a novel point mutation in connexin 50–L7Q. Mol Vis 14:823–828PubMedPubMedCentralGoogle Scholar
  33. Liu J, Ek Vitorin JF, Weintraub ST, Gu S, Shi Q, Burt JM, Jiang JX (2011) Phosphorylation of connexin 50 by protein kinase A enhances gap junction and hemichannel function. J Biol Chem 286(19):16914–16928CrossRefPubMedPubMedCentralGoogle Scholar
  34. Liu X, Wu C, Li C, Boerwinkle E (2016) dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum Mutat 37(3):235–241CrossRefPubMedPubMedCentralGoogle Scholar
  35. Ma AS, Grigg JR, Ho G, Prokudin I, Farnsworth E, Holman K, Cheng A, Billson FA, Martin F, Fraser C et al (2016) Sporadic and familial congenital cataracts: mutational spectrum and new diagnoses using next-generation sequencing. Hum Mutat 37(4):371–384CrossRefPubMedPubMedCentralGoogle Scholar
  36. 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(1):155–159CrossRefPubMedGoogle Scholar
  37. Mackay DS, Bennett TM, Culican SM, Shiels A (2014) Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract. Hum Genomics 8:19CrossRefPubMedPubMedCentralGoogle Scholar
  38. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303CrossRefPubMedPubMedCentralGoogle Scholar
  39. Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D et al (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 359(16):1685–1699CrossRefPubMedPubMedCentralGoogle Scholar
  40. Mohebi M, Chenari S, Akbari A, Ghassemi F, Zarei-Ghanavati M, Fakhraie G, Babaie N, Heidari M (2017) Mutation analysis of connexin 50 gene among Iranian families with autosomal dominant cataracts. Iran J Basic Med Sci 20(3):288–293PubMedPubMedCentralGoogle Scholar
  41. Mose LE, Wilkerson MD, Hayes DN, Perou CM, Parker JS (2014) ABRA: improved coding indel detection via assembly-based realignment. Bioinformatics 30(19):2813–2815CrossRefPubMedPubMedCentralGoogle Scholar
  42. Pfenniger A, Wohlwend A, Kwak BR (2011) Mutations in connexin genes and disease. Eur J Clin Invest 41(1):103–116CrossRefPubMedGoogle Scholar
  43. Ponnam SP, Ramesha K, Tejwani S, Ramamurthy B, Kannabiran C (2007) Mutation of the gap junction protein alpha 8 (GJA8) gene causes autosomal recessive cataract. J Med Genet 44(7):e85CrossRefPubMedPubMedCentralGoogle Scholar
  44. Ponnam SP, Ramesha K, Matalia J, Tejwani S, Ramamurthy B, Kannabiran C (2013) Mutational screening of Indian families with hereditary congenital cataract. Mol Vis 19:1141–1148PubMedPubMedCentralGoogle Scholar
  45. Prokudin I, Simons C, Grigg JR, Storen R, Kumar V, Phua ZY, Smith J, Flaherty M, Davila S, Jamieson RV (2014) Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1. Eur J Hum Genet 22(7):907–915CrossRefPubMedGoogle Scholar
  46. Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26(6):841–842CrossRefPubMedPubMedCentralGoogle Scholar
  47. Reis LM, Semina EV (2015) Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma. Birth Defects Res C Embryo Today 105(2):96–113CrossRefPubMedPubMedCentralGoogle Scholar
  48. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424CrossRefPubMedPubMedCentralGoogle Scholar
  49. Rong P, Wang X, Niesman I, Wu Y, Benedetti LE, Dunia I, Levy E, Gong X (2002) Disruption of Gja8 (alpha8 connexin) in mice leads to microphthalmia associated with retardation of lens growth and lens fiber maturation. Development 129(1):167–174PubMedGoogle Scholar
  50. Rosenfeld JA, Traylor RN, Schaefer GB, McPherson EW, Ballif BC, Klopocki E, Mundlos S, Shaffer LG, Aylsworth AS, Group qS (2012) Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes. Eur J Hum Genet 20(7):754–761CrossRefPubMedPubMedCentralGoogle Scholar
  51. Schmidt W, Klopp N, Illig T, Graw J (2008) A novel GJA8 mutation causing a recessive triangular cataract. Mol Vis 14:851–856PubMedPubMedCentralGoogle Scholar
  52. Shah SP, Taylor AE, Sowden JC, Ragge NK, Russell-Eggitt I, Rahi JS, Gilbert CE, Group SoEAS-USI (2011) Anophthalmos, microphthalmos, and typical coloboma in the United Kingdom: a prospective study of incidence and risk. Invest Ophthalmol Vis Sci 52(1):558–564CrossRefPubMedGoogle Scholar
  53. Shah SP, Taylor AE, Sowden JC, Ragge N, Russell-Eggitt I, Rahi JS, Gilbert CE, Group SoEASI (2012) Anophthalmos, microphthalmos, and Coloboma in the United Kingdom: clinical features, results of investigations, and early management. Ophthalmology 119(2):362–368CrossRefPubMedGoogle Scholar
  54. Shiels A, Hejtmancik JF (2017) Mutations and mechanisms in congenital and age-related cataracts. Exp Eye Res 156:95–102CrossRefPubMedGoogle Scholar
  55. Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, Clawson H, Spieth J, Hillier LW, Richards S et al (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15(8):1034–1050CrossRefPubMedPubMedCentralGoogle Scholar
  56. Siepel A, Pollard KS, Haussler D (2006) New methods for detecting lineage-specific selection. In: Apostolico A, Guerra C, Istrail S, Pevzner PA, Waterman M (eds) Research in computational molecular biology. RECOMB 2006. Lecture Notes in Computer Science, vol 3909. Springer, Berlin, pp 190–205Google Scholar
  57. Skalicky SE, White AJ, Grigg JR, Martin F, Smith J, Jones M, Donaldson C, Smith JE, Flaherty M, Jamieson RV (2013) Microphthalmia, anophthalmia, and coloboma and associated ocular and systemic features: understanding the spectrum. JAMA Ophthalmol 131(12):1517–1524CrossRefPubMedGoogle Scholar
  58. Slavotinek AM (2011) Eye development genes and known syndromes. Mol Genet Metab 104(4):448–456CrossRefPubMedPubMedCentralGoogle Scholar
  59. Stankiewicz P, Lupski JR (2010) Structural variation in the human genome and its role in disease. Annu Rev Med 61:437–455CrossRefPubMedGoogle Scholar
  60. Steele EC, Lyon MF, Favor J, Guillot PV, Boyd Y, Church RL (1998) A mutation in the connexin 50 (Cx50) gene is a candidate for the No2 mouse cataract. Curr Eye Res 17(9):883–889CrossRefPubMedGoogle Scholar
  61. Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE et al (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455(7210):232–236CrossRefPubMedPubMedCentralGoogle Scholar
  62. Sun W, Xiao X, Li S, Guo X, Zhang Q (2011) Mutational screening of six genes in Chinese patients with congenital cataract and microcornea. Mol Vis 17:1508–1513PubMedPubMedCentralGoogle Scholar
  63. The 1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA et al (2015) A global reference for human genetic variation. Nature 526(7571):68–74CrossRefPubMedCentralGoogle Scholar
  64. Tong JJ, Minogue PJ, Guo W, Chen TL, Beyer EC, Berthoud VM, Ebihara L (2011) Different consequences of cataract-associated mutations at adjacent positions in the first extracellular boundary of connexin50. Am J Physiol Cell Physiol 300(5):C1055–C1064CrossRefPubMedPubMedCentralGoogle Scholar
  65. Vanita V, Singh JR, Singh D, Varon R, Sperling K (2008) A novel mutation in GJA8 associated with jellyfish-like cataract in a family of Indian origin. Mol Vis 14:323–326PubMedPubMedCentralGoogle Scholar
  66. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164CrossRefPubMedPubMedCentralGoogle Scholar
  67. Wang Z, Han J, David LL, Schey KL (2013) Proteomics and phosphoproteomics analysis of human lens fiber cell membranes. Invest Ophthalmol Vis Sci 54(2):1135–1143CrossRefPubMedPubMedCentralGoogle Scholar
  68. White TW (2002) Unique and redundant connexin contributions to lens development. Science 295(5553):319–320CrossRefPubMedGoogle Scholar
  69. White TW, Goodenough DA, Paul DL (1998) Targeted ablation of connexin50 in mice results in microphthalmia and zonular pulverulent cataracts. J Cell Biol 143(3):815–825CrossRefPubMedPubMedCentralGoogle Scholar
  70. Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, van Kogelenberg M, King DA, Ambridge K, Barrett DM, Bayzetinova T et al (2015) Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet 385(9975):1305–1314CrossRefPubMedPubMedCentralGoogle Scholar
  71. Xia CH, Liu H, Cheung D, Cheng C, Wang E, Du X, Beutler B, Lo WK, Gong X (2006) Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development and cataractogenesis. Development 133(10):2033–2040CrossRefPubMedGoogle Scholar
  72. Xia CH, Chang B, Derosa AM, Cheng C, White TW, Gong X (2012) Cataracts and microphthalmia caused by a Gja8 mutation in extracellular loop 2. PLoS ONE 7(12):e52894CrossRefPubMedPubMedCentralGoogle Scholar
  73. Yasue A, Kono H, Habuta M, Bando T, Sato K, Inoue J, Oyadomari S, Noji S, Tanaka E, Ohuchi H (2017) Relationship between somatic mosaicism of Pax6 mutation and variable developmental eye abnormalities-an analysis of CRISPR genome-edited mouse embryos. Sci Rep 7(1):53CrossRefPubMedPubMedCentralGoogle Scholar
  74. Yu Y, Wu M, Chen X, Zhu Y, Gong X, Yao K (2016) Identification and functional analysis of two novel connexin 50 mutations associated with autosome dominant congenital cataracts. Sci Rep 6:26551CrossRefPubMedPubMedCentralGoogle Scholar
  75. Yuan L, Sui T, Chen M, Deng J, Huang Y, Zeng J, Lv Q, Song Y, Li Z, Lai L (2016) CRISPR/Cas9-mediated GJA8 knockout in rabbits recapitulates human congenital cataracts. Sci Rep 6:22024CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Fabiola Ceroni
    • 1
  • Domingo Aguilera-Garcia
    • 2
    • 3
  • Nicolas Chassaing
    • 4
    • 5
  • Dorine Arjanne Bax
    • 1
  • Fiona Blanco-Kelly
    • 2
    • 3
    • 6
    • 7
  • Patricia Ramos
    • 2
    • 3
  • Maria Tarilonte
    • 2
    • 3
  • Cristina Villaverde
    • 2
    • 3
  • Luciana Rodrigues Jacy da Silva
    • 2
    • 3
  • Maria Juliana Ballesta-Martínez
    • 8
  • Maria Jose Sanchez-Soler
    • 8
  • Richard James Holt
    • 1
  • Lisa Cooper-Charles
    • 9
  • Jonathan Bruty
    • 9
  • Yvonne Wallis
    • 9
  • Dominic McMullan
    • 9
  • Jonathan Hoffman
    • 10
  • David Bunyan
    • 11
  • Alison Stewart
    • 12
  • Helen Stewart
    • 6
  • Katherine Lachlan
    • 13
    • 14
  • DDD Study
    • 15
  • Alan Fryer
    • 16
  • Victoria McKay
    • 16
  • Joëlle Roume
    • 17
  • Pascal Dureau
    • 18
  • Anand Saggar
    • 19
  • Michael Griffiths
    • 9
  • Patrick Calvas
    • 4
    • 5
  • Carmen Ayuso
    • 2
    • 3
  • Marta Corton
    • 2
    • 3
  • Nicola K Ragge
    • 1
    • 10
    Email author
  1. 1.Faculty of Health and Life SciencesOxford Brookes UniversityOxfordUK
  2. 2.Genetics ServiceInstituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM)MadridSpain
  3. 3.Centre for Biomedical Network Research on Rare Diseases (CIBERER)ISCIIIMadridSpain
  4. 4.Service de Génétique Médicale, Hôpital PurpanCHU ToulouseToulouseFrance
  5. 5.UMR 1056 InsermUniversité de ToulouseToulouseFrance
  6. 6.Oxford Centre for Genomic MedicineOxford University Hospitals NHS Foundation TrustOxfordUK
  7. 7.Institute of OphthalmologyUniversity College LondonLondonUK
  8. 8.Medical Genetics DepartmentUniversity Hospital Virgen de la ArrixacaMurciaSpain
  9. 9.West Midlands Regional Genetics LaboratoryBirmingham Women’s and Children’s NHS Foundation TrustBirminghamUK
  10. 10.West Midlands Regional Clinical Genetics Service and Birmingham Health PartnersBirmingham Women’s and Children’s NHS Foundation TrustBirminghamUK
  11. 11.Wessex Regional Genetics LaboratorySalisbury NHS Foundation TrustSalisburyUK
  12. 12.Sheffield Clinical Genetics DepartmentNorthern General HospitalSheffieldUK
  13. 13.Wessex Clinical Genetics Service, Princess Anne HospitalUniversity Hospital Southampton NHS Foundation TrustSouthamptonUK
  14. 14.Human Genetics and Genomic Medicine, Southampton General HospitalUniversity of SouthamptonSouthamptonUK
  15. 15.Wellcome Trust Sanger InstituteCambridgeUK
  16. 16.Cheshire and Merseyside Genetics ServiceLiverpool Women’s NHS Foundation TrustLiverpoolUK
  17. 17.Department of Clinical Genetics, Centre de Référence “AnDDI Rares”Poissy Hospital GHU PIFOPoissyFrance
  18. 18.Fondation Ophtalmologique Adolphe-de-RothschildParisFrance
  19. 19.Clinical Genetics UnitSt Georges University of LondonLondonUK

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