iSyTE: integrated Systems Tool for Eye gene discovery.

PURPOSE To facilitate the identification of genes associated with cataract and other ocular defects, the authors developed and validated a computational tool termed iSyTE (integrated Systems Tool for Eye gene discovery; http://bioinformatics.udel.edu/Research/iSyTE). iSyTE uses a mouse embryonic lens gene expression data set as a bioinformatics filter to select candidate genes from human or mouse genomic regions implicated in disease and to prioritize them for further mutational and functional analyses. METHODS Microarray gene expression profiles were obtained for microdissected embryonic mouse lens at three key developmental time points in the transition from the embryonic day (E)10.5 stage of lens placode invagination to E12.5 lens primary fiber cell differentiation. Differentially regulated genes were identified by in silico comparison of lens gene expression profiles with those of whole embryo body (WB) lacking ocular tissue. RESULTS Gene set analysis demonstrated that this strategy effectively removes highly expressed but nonspecific housekeeping genes from lens tissue expression profiles, allowing identification of less highly expressed lens disease-associated genes. Among 24 previously mapped human genomic intervals containing genes associated with isolated congenital cataract, the mutant gene is ranked within the top two iSyTE-selected candidates in approximately 88% of cases. Finally, in situ hybridization confirmed lens expression of several novel iSyTE-identified genes. CONCLUSIONS iSyTE is a publicly available Web resource that can be used to prioritize candidate genes within mapped genomic intervals associated with congenital cataract for further investigation. Extension of this approach to other ocular tissue components will facilitate eye disease gene discovery.

[1]  Thomas M. Bennett,et al.  Cat-Map: putting cataract on the map , 2010, Molecular vision.

[2]  J. Rahi,et al.  Congenital and infantile cataract in the United Kingdom: underlying or associated factors. British Congenital Cataract Interest Group. , 2000, Investigative ophthalmology & visual science.

[3]  W. Xu,et al.  An autosomal dominant cataract locus mapped to 19q13-qter in a Chinese family , 2011, Molecular vision.

[4]  D. Schorderet,et al.  Gene localization for aculeiform cataract, on chromosome 2q33-35. , 1998, American journal of human genetics.

[5]  M. Warburg,et al.  Assignment of congenital cataract Volkmann type (CCV) to chromosome 1p36 , 1995, Human Genetics.

[6]  Seth Blackshaw,et al.  Comprehensive Analysis of Photoreceptor Gene Expression and the Identification of Candidate Retinal Disease Genes , 2001, Cell.

[7]  S. Riazuddin,et al.  Mutations in betaB3-crystallin associated with autosomal recessive cataract in two Pakistani families. , 2005, Investigative ophthalmology & visual science.

[8]  S. Bhattacharya,et al.  Connexin46 mutations in autosomal dominant congenital cataract. , 1999, American journal of human genetics.

[9]  Shaheen N. Khan,et al.  A new locus for autosomal recessive congenital cataract identified in a Pakistani family , 2010, Molecular vision.

[10]  Yanhua Qi,et al.  A new locus for inherited nuclear cataract mapped to the long arm of chromosome 1. , 2007, Molecular vision.

[11]  Kapil Bharti,et al.  Expression profiling during ocular development identifies 2 Nlz genes with a critical role in optic fissure closure , 2009, Proceedings of the National Academy of Sciences.

[12]  M. Kaiser-Kupfer,et al.  Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11-12. , 1995, American journal of human genetics.

[13]  R. Maas,et al.  Lens induction in vertebrates: variations on a conserved theme of signaling events. , 2006, Seminars in cell & developmental biology.

[14]  S. Bhattacharya,et al.  A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant "zonular pulverulent" cataract, on chromosome 1q. , 1998, American journal of human genetics.

[15]  D. Schorderet,et al.  A new locus for congenital cataract, microcornea, microphthalmia, and atypical iris coloboma maps to chromosome 2. , 2009, Ophthalmology.

[16]  G. Silvestri,et al.  Fine mapping of the keratoconus with cataract locus on chromosome 15q and candidate gene analysis. , 2006, Molecular vision.

[17]  E. Bermejo,et al.  Congenital eye malformations: clinical-epidemiological analysis of 1,124,654 consecutive births in Spain. , 1998, American journal of medical genetics.

[18]  M. Frydman,et al.  A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family. , 2002, American journal of human genetics.

[19]  P. Brown,et al.  Differential gene expression in anatomical compartments of the human eye , 2005, Genome Biology.

[20]  Russ B. Altman,et al.  Bioinformatics challenges for personalized medicine , 2011, Bioinform..

[21]  J. Gécz,et al.  A novel syndrome of paediatric cataract, dysmorphism, ectodermal features, and developmental delay in Australian Aboriginal family maps to 1p35.3-p36.32 , 2010, BMC Medical Genetics.

[22]  P. Sharpe,et al.  Tooth Agenesis: from Molecular Genetics to Molecular Dentistry , 2008, Journal of dental research.

[23]  B. Kerr,et al.  Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma. , 2002, Human molecular genetics.

[24]  J. Hejtmancik,et al.  Autosomal recessive juvenile onset cataract associated with mutation in BFSP1 , 2007, Human Genetics.

[25]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[26]  R. Maas,et al.  Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode. , 1997, Development.

[27]  P. Kramer,et al.  A second gene for cerulean cataracts maps to the beta crystallin region on chromosome 22. , 1996, Genomics.

[28]  Mugen Liu,et al.  Identification of a genetic locus for autosomal dominant infantile cataract on chromosome 20p12.1-p11.23 in a Chinese family , 2008, Molecular vision.

[29]  K. Friend,et al.  A novel locus for X-linked congenital cataract on Xq24 , 2008, Molecular vision.

[30]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[31]  M. Frydman,et al.  A nonsense mutation in the glucosaminyl (N-acetyl) transferase 2 gene (GCNT2): association with autosomal recessive congenital cataracts. , 2004, Investigative ophthalmology & visual science.

[32]  Shaheen N. Khan,et al.  Mapping of a novel locus associated with autosomal recessive congenital cataract to chromosome 8p , 2010, Molecular vision.

[33]  S. Khaliq,et al.  A novel locus for autosomal dominant nuclear cataract mapped to chromosome 2p12 in a Pakistani family. , 2001, Investigative ophthalmology & visual science.

[34]  J. Hejtmancik.  Congenital cataracts and their molecular genetics. , 2008, Seminars in cell & developmental biology.

[35]  Lin He,et al.  A novel locus of coralliform cataract mapped to chromosome 2p24-pter , 2005, Journal of Human Genetics.

[36]  Martha L Bulyk,et al.  Precise temporal control of the eye regulatory gene Pax6 via enhancer-binding site affinity. , 2010, Genes & development.

[37]  Antoon F. M. Moorman,et al.  More than a decade of developmental gene expression atlases: where are we now? , 2009, Nucleic acids research.

[38]  H. Fuchs,et al.  Mutation in a novel connexin-like gene (Gjf1) in the mouse affects early lens development and causes a variable small-eye phenotype. , 2008, Investigative ophthalmology & visual science.

[39]  S. Riazuddin,et al.  Localization of autosomal recessive congenital cataracts in consanguineous Pakistani families to a new locus on chromosome 1p. , 2007, Molecular vision.

[40]  S. Bhattacharya,et al.  Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans. , 2001, American journal of human genetics.

[41]  J. Hess,et al.  Autosomal-dominant congenital cataract associated with a deletion mutation in the human beaded filament protein gene BFSP2. , 2000, American journal of human genetics.

[42]  J. Graw.  Mouse models of cataract , 2009, Journal of Genetics.

[43]  A. Paterson,et al.  CRYBA4, a novel human cataract gene, is also involved in microphthalmia. , 2006, American journal of human genetics.

[44]  S. Bhattacharya,et al.  A locus for autosomal dominant anterior polar cataract on chromosome 17p. , 1996, Human molecular genetics.

[45]  K. Lampi,et al.  A nonsense mutation in CRYBB1 associated with autosomal dominant cataract linked to human chromosome 22q. , 2002, American journal of human genetics.

[46]  B. J. Klevering,et al.  Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa. , 2011, American journal of human genetics.

[47]  D. Mackey,et al.  Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract , 2009, Human mutation.

[48]  Z. Li,et al.  Gamma-S crystallin gene (CRYGS) mutation causes dominant progressive cortical cataract in humans , 2005, Journal of Medical Genetics.

[49]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[50]  Jun Miyoshi,et al.  The cell adhesion gene PVRL3 is associated with congenital ocular defects , 2011, Human Genetics.

[51]  Benjamin M. Bolstad,et al.  affy - analysis of Affymetrix GeneChip data at the probe level , 2004, Bioinform..

[52]  C. Krellner,et al.  Emerging local Kondo screening and spatial coherence in the heavy-fermion metal YbRh2Si2 , 2011, Nature.

[53]  Colin A. Johnson,et al.  Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. , 2011, American journal of human genetics.

[54]  M. Kantorow,et al.  Mutations in FYCO1 cause autosomal-recessive congenital cataracts. , 2011, American journal of human genetics.

[55]  S. Kaushal,et al.  Missense mutations in MIP underlie autosomal dominant ‘polymorphic’ and lamellar cataracts linked to 12q , 2000, Nature Genetics.

[56]  M. Spence,et al.  A new locus for autosomal dominant cataract on chromosome 19: linkage analyses and screening of candidate genes. , 2006, Investigative ophthalmology & visual science.

[57]  Fowzan S Alkuraya,et al.  Mutations in the RNA Granule Component TDRD7 Cause Cataract and Glaucoma , 2011, Science.

[58]  S. Resnikoff,et al.  Global data on visual impairment in the year 2002. , 2004, Bulletin of the World Health Organization.

[59]  M. Hayden,et al.  Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract , 2002, Nature Genetics.

[60]  Shaheen N. Khan,et al.  Mapping of a new locus associated with autosomal recessive congenital cataract to chromosome 3q , 2010, Molecular vision.

[61]  J. Kivlin,et al.  A progressive early onset cataract gene maps to human chromosome 17q24 , 1995, Nature Genetics.

[62]  S. Sel,et al.  WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. , 2009, American journal of human genetics.

[63]  N. Niikawa,et al.  CHMP4B, a novel gene for autosomal dominant cataracts linked to chromosome 20q. , 2007, American journal of human genetics.

[64]  P. Kramer,et al.  Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA. , 1998, Human molecular genetics.

[65]  R. Maas,et al.  Building the developmental oculome: systems biology in vertebrate eye development and disease , 2010, Wiley interdisciplinary reviews. Systems biology and medicine.

[66]  Vasilis Vasiliou,et al.  Multiple and Additive Functions of ALDH3A1 and ALDH1A1 , 2007, Journal of Biological Chemistry.