Epidemiologyandmoleculargeneticsofcongenitalcataracts 窑Review窑 Epidemiologyandmoleculargeneticsofcongenital cataracts

1DepartmentofVascularEndocrineSurgery,XijingHospital, INTRODUCTION FourthMilitaryMedicalUniversity,Xi'an 710032, Shaanxi aediatriccataractisamajorcauseofchildhood Province,China P blindness. Severalgeneshavebeenidentifiedin 2Department of Respiratory,XijingHospital,Fourth Military associationwithcongenitalandpaediatriccataracts.The MedicalUniversity,Xi'an710032,ShaanxiProvince,China aimwastodeterminetheincidenceofcataractina 3DepartmentofAnatomyandEditorialOfficeofChineseJournalof population,theproportionofhereditarycataracts,themode Neuroanatomy,FourthMilitaryMedicalUniversity,Xi'an710032, ofinheritance,andtheclinicalpresentation.Congenital ShaanxiProvince,China cataractiscommonwithvisualdisabilityinchildren,dueto 4OutpatientDepartmentofOncology,InstituteofTumour,Fourth abnormalmetabolismofembryoniclenstransparencyresults MilitaryMedicalUniversity,Xi'an710032,ShaanxiProvince, asevere blindingdisease.Pathogenesisofcongenital China cataractisconsideredcomplexwith1/4-1/3familyheredity. Correspondenceto: Zhi-KuiLi.Department ofRespiratory, Congenitalcataractcanoccurinisolation,oraseye XijingHospital,FourthMilitaryMedicalUniversity,Xi'an710032, syndromeanddevelopmentaldefects.Amulti-systemper- ShaanxiProvince,China;Chang-TaiXu.EditorialOfficeChinese formancecanbesecondarytosystemicmetabolicdisease[1-3]. JournalofNeuroanatomy,FourthMilitaryMedicalUniversity, Lensdevelopmentdependsonacombinationofgenesand Xi'an710032,ShaanxiProvince,[email protected] theirproductsintimeand spacetocompletethe Received:2011-06-25 Accepted:2011-07-10 coordinationroleoftheguidance. Thelenstransmitslightofwavelengthsfrom390nmto Abstract 1200nmefficiently,extendingwellabovethelimitofvisual perception(about720nm).Lenstransparencyresultsfrom ·Congenitalcataractisacrystallinsevereblindingdisease appropriatearchitectureoflenscellsandtightpackingof andgeneticfactorsindiseasedevelopmentareimportant. theirproteins,resultinginaconstantrefractiveindexover Crystallingrowthisunderacombinationofgenesandtheir distancesapproximatingthe wavelengthoflight [1]. productsintimeandspacetocompletethecoordinationrole Ultrastructurally,thelenscomprisesananteriorlayerof oftheguidance.Congenitalcataract-relatedgenes,included organellerichcuboidalepithelialcellscoveringalargefiber crystallinproteingene(CRYAA,CRYAB,CRYBA1/A3,CRYBA4, cellmassmakingupthebulkofthelens(Figure1).Layers CRYBB1,CRYBB2,CRYBB3,CRYGC,CRYGD,CRYGS),gap junctionchannelproteingene(GJA1,GJA3,GJA8), membraneproteingene(GJA3,GJA8,MIP,LIM2), cytoskeletalproteingene(BF-SP2),transcriptionfactorgenes (HSF4,MAF,PITX3,PAX6),ferritinlightchaingene(FTL), fibroblastgrowthfactor(FGF)andsoon.Currently,thereare about39geneticlociisolatedtowhichprimarycataractshave beenmapped,althoughthenumberisconstantlyincreasing anddependstosomeextentondefinition.Wesummarized therecentadvancesonepidemiologyandgeneticlocationsof congenitalcataractinthisreview. · KEYWORDS:congenitalcataract;crystallinproteingene; Figure1 Structureofthematurehumanlens Celldivision gapjunctionchannelproteingene;membraneproteingene; occursinthe10and2O'clockpositionsoftheanteriorepithelia, cytoskeletonprotein;transcriptionfactorgenes;ferritinlight andcellsmovelaterallyuntiltheyinvertinthebowregionofthe chaingene;growthfactorgene lensandbeginloosingtheirorganellestoformcorticalfibercells. DOI:10.3980/j.issn.2222-3959.2011.04.20 Nuclearfibercellsarelaiddownrelativelyearlyindevelopment. Theendsofthemoreperipheralfibercellsmeetanthesutures, shownhereasverticallinesbutseenclinicallyasanteriorand YiJ,YunJ,LiZK,XuCT,PanBR.Epidemiologyandmolecular posteriorYstructures geneticsofcongenitalcataracts. 2011;4(4):422-432 422 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 4熏晕燥援 4熏 Aug.18, 圆园11 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-83085628 耘皂葬蚤造押陨允韵援圆园园园岳员远猿援糟燥皂

Figure2Congenitalcataracts A:Slitlampviewofadenseanteriorpolarcataract;B:Reflexviewofposteriorsubcapsularcataract;C: Densenuclearcataract;D:Punctatenuclearcataract;E:Reflexviewofalamellarpulverulentcataractwithacorticalriderintheupperright; F:Suturalcataractwithapulverulentnuclearlamellarcomponent ofnucleatedcorticalfibercellsformhighlyordered approximately70%ofcongenitalcataracts [3].Conversely, concentricshellsaroundthenon-nucleatedandessentially lensopacitiesmaybeassociated withotherocular organelle-freecentralfibercellswhichmakeupthelens anomaliessuchasmicrophthalmia,aniridia,otheranterior nucleus.Theendsofthemoreperipheralfibercellsabuton chamberdevelopmentalanomalies,orretinaldegenerations, branched anteriorandposteriorsutures.Thecellular seeninapproximately15%ofcases.Cataractsmayalsobe architecture andarrangementofthefibercellsand partofmultisystemgeneticdisorderssuchaschromosome particularlytheirsuturesarecriticalforlighttransmission abnormalities,Lowesyndromeorneurofibromatosistype2, andlenstransparency [2].Inaddition,thestabilityandclose also accountingforapproximately15%ofcongenital orderingoflenscrystallins,whichmakeup80-90%ofthe cataracts.Insomecasesthisdistinctioncanbeblurred, soluble proteinsinthelens,arecriticalforlens inthe developmentalabnormalityanteriorsegment transparency.Thehighproteincontentofthelensand mesenchymaldysgenesisresultingfromabnormalitiesinthe especiallythelensnucleus,approximately60%ofthewet PITX3gene,inheritedcataractsmaybeisolatedinsome weight,thehighestofanytissue,isparticularlyimportant familymembersandassociatedwithadditionalfindingsin forrefractionandfocusingoflight.Solutionsoflens others.Inanattempttodevelopalogicalclassificationof crystallinsarehighlytransparent,andastheyare congenitalcataracts,Merinhasproposedasystembasedon concentratedtolevelsabove450mg/mL,lightscattering morphological classification. Examplesareshownin actuallydecreases[1-3]. Figure2[1]. Cataractscanbedefinedbytheageatonset:acongenitalor EPIDEMIOLOGYANDETIOLOGY infantilecataractpresentswithinthefirstyearoflife;a Epidemiology Cataractistheopacificationoftheeyelens juvenilecataractpresentswithinthefirstdecadeoflife;a andbasedupontheageatappearance.Cataractcanbe presenilecataractpresentsbeforetheageofabout45years, classifiedascongenital,infantile,juvenile,presenileand andsenileorage-relatedcataractafterthat.Between8.3 senile.Pediatriccataractsareresponsibleformorethan1 and25percentofcongenitalcataractsarebelievedtobe millionchildhoodblindnessinAsia.Indevelopingcountries inherited.Thelensalonemaybeinvolved,accountingfor likeIndia,7.4-15.3%ofchildhoodblindnessisdueto 423 Epidemiologyandmoleculargeneticsofcongenitalcataracts cataract.Theprevalenceofcataractinchildrenhasbeen Todescribetheprevalenceandriskfactorsforcataractinan estimatedbetween1-15/10,000 children.Hereditary, Australianpopulationaged40yearsandolder,McCarty metabolicandotherocularorsystemicdisordersandtrauma [10] haveshownthatcataractisapublichealthproblemin areknownfactorsresponsibleforcataractinchildren.In Australia,which,likeotherdeveloped countries,is India,halfofallchildhoodcataractsareIdiopathic.Outof experiencingademographicshifttowardmoreelderly 172children,88.4%hadnon-traumaticcataractand11.6% peopleinthepopulation.Thefirststepinthedesignofan hadtraumaticcataracts.Amongnon-traumaticcataracts, appropriateresponsetotheexpectedincreaseinthenumber 7.2%werehereditary,4.6%wereduetocongenitalrubella ofcasesofcataractistodescribe theage-specific syndrome,15.1%weresecondaryand73.0% were prevalenceandriskfactorsofcataract.Manyoftherisk undetermined.Inthegroupofundeterminedcases,during factorsthatweidentifiedinthepopulationarepotentially pregnancy67%ofthemotherhadhistoryofillness,and modifiablethroughpublichealthcampaigns[11-14]. 22%hadtakenmedicationsduringpregnancy.Inadequate Etiology Manyetiologicalstudiesonchildhoodcataract awarenessofthecausativefactorsofcataractswithinthe havebeencarriedoutindevelopedaswellasdeveloping societyhasleadtoincreaseofcataractsinchildren[4-6]. countriestodeterminecausativefactors.Studiesperformed Considerableprogresshasbeenmadeincharacterizing invariouspartsofIndiashowvariationinetiologicalfactors phenotypes,determiningtheprevalenceandincidencein affectingchildhoodcataract.Insouth Indiaamong variouspopulationgroups,andunderstandingriskfactors non-traumaticcataracts,25%wereduetohereditary,15% forcataract.Cataractsurgeryresearchhasdocumented wereduetocongenitalrubellasyndromeand51%were functionalimprovementsfollowingsurgery[5-7].Cataractisan idiopathic.Nearlyhalfofnon-traumaticcataractsinthis independentmarkerofearlymortality,providingapossible populationareduetopotentiallypreventablecauseslike systemtostudytheagingprocess.Promisingfutureworkin congenitalrubellasyndromeand autosomaldominant cataractepidemiologyishighlighted.Despitetheavailability disease. ofcataractsurgery,cataractisstilltheleadingcauseof Inthepaediatriccataractpopulationexamined, blindnessworldwide.Fromapublichealthstandpoint, approximatelyhalfofthepatientswerediagnosedinthe research thatcanidentifyways todelayonsetor firstyearoflife.Morethan18%hadapositivefamily progression,orachievetheholygrailofpreventionof historyofcataracts.Ofpatientswithhereditarycataracts8% cataract,shouldremainaleadingpriority[7]. presentedwithunilateralinvolvement.Identificationofthe Foster [8] reportedthatcataractisthemostimportant genesthatcausepaediatricandcongenitalcataractshould causeoftreatablechildhoodblindness.Thereare200000 helpclarifytheaetiologyofsomesporadicandunilateral childrenblindfromcataractworldwide,and20000to40000 cataracts.TheresultsshowedbyWirth [15] that421 childrenwithdevelopmentalbilateralcataractareborneach patientswithpaediatriccataractwereidentified,whichgives year.Rubellaisstillanimportantcauseofpreventable anestimatedincidenceof2.2per10,000births.Ofthe342 diseaseinmanycountries.Inthedevelopingworld,thereis affectedindividualswithanegativefamilyhistory,50% aneedtoimproveearlycasedetectionandreferralservices werediagnosedduringthefirstyearoflife,and56/342 andtoestablishcenterswithexpertiseintheassessment, (16%)wereassociatedwitharecognisedsystemicdisease surgicaltreatment,andlong-termmanagementofthechild orsyndrome.Unilateralcataractwasidentifiedin178/342 withcataract. Blindnessdueto cataractpresentsan (52%)ofsporadiccases.Seventy-ninechildren(from54 enormousprobleminIndianotonlyintermsofhuman nuclearfamilies)hadapositivefamilyhistory.Ofthese54 morbiditybutalsointermsofeconomiclossandsocial families,45wererecruitedforclinicalexaminationand burden.TheWHO/NPCB(NationalProgrammeforControl DNAcollection.Tennuclearfamiliesweresubsequently ofBlindness)surveyhasshownthatthereisabacklogof foundtoberelated,resultinginfourlargerpedigrees.Thus, over22millionblindeyes(12millionblindpeople)in 39familieshavebeenstudied.Themodeofinheritancewas India,and80.1%oftheseareblindduetocataract.The autosomaldominantin30families,Xlinkedinfour, annualincidenceofcataractblindnessisabout3.8million. autosomalrecessiveintwo,anduncertaininthree.Intotal, Thepresentannuallevelofperformanceisintheorderof 178affectedfamilymemberswereexamined;ofthese8% about1.6-1.9millioncataractoperations.Toclearthe presentedwithunilateralcataractsand43%werediagnosed backlogofcataractcasesbytheyear2000andtotacklethe withinthefirstyearoflife[12-14]. risingincidence,5-6millioncataractoperationsannually Cataractisresponsibleforabout10%blindnessamong willhavetobeperformedasagainstthepresentrateof1.7 childreninIndia.Etiologyofcataractisnotwelldefined millionperyear[9]. especiallyforchildhoodcataractsandepidemiologicaldata 424 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 4熏晕燥援 4熏 Aug.18, 圆园11 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-83085628 耘皂葬蚤造押陨允韵援圆园园园岳员远猿援糟燥皂 forIndianpopulationisnotavailableindetails.Outof172 super A-,whichisviableinamouseskeletal 琢 children,88.4%hadnon-traumaticcataractand11.6%had musclecellline,withnormal A-crystallinshowsthatithas 琢 traumaticcataracts.Amongnon-traumaticcataracts,7.2% diminished thermostability, increased exposureof werehereditary,4.6%wereduetocongenitalrubella hydrophobicpatches,alargercomplexsizeandlostits syndrome,15.1%weresecondaryand 73.0%were chaperoneactivity.However,super A-crystallinsubunits 琢 undetermined.Inthegroupofundeterminedcases,during exchangeasreadilybetweencomplexesasdoesnormal pregnancy67%ofthemotherhadhistoryofillness,and A-crystallin.These data indicatethat chaperone-like 琢 22%hadtakenmedicationsduringpregnancy.Health activitymayvanishindependentofsubunithydrophobicity educationofwomentochildbearingageandschoolchildren andexchangeability [19,20].Crystallinsareseparatedintotwo candecreaseincidenceofpediatriccataracts[16]. classes:taxon-specific,orenzyme,andubiquitous.The MOLECULARGENETICS latterclassconstitutesthemajorproteinsofvertebrateeye Cataractscanbeisolatedorcanoccurinassociationwitha lensandmaintainsthetransparencyandrefractiveindexof largenumberofmetabolicdiseasesandgeneticsyndromes[17]. thelens.Sincelenscentralfibercellslosetheirnuclei Isolatedcongenitalcataractstendtobehighlypenetrant duringdevelopment,thesecrystallinsaremadeandthen Mendeliantraits,withautosomaldominantmorecommon retainedthroughoutlife,makingthemextremelystable thanautosomalrecessivecataracts.Currently,thereare .Mammalianlenscrystallinsaredividedinto , , 琢 茁 about39geneticlocitowhichisolatedorprimarycataracts and families;Betaand crystallinsarealsoconsideredas 酌 酌 havebeenmapped,althoughthenumberisconstantly asuperfamily.Alphaand familiesarefurtherdividedinto 茁 increasinganddependstosomeextentondefinition(Table1). acidicandbasicgroups.Sevenproteinregionsexistin Ofthese,severalareassociatedwithadditionalabnormalities, :fourhomologousmotifs,aconnectingpeptide, mostlyaspartofdevelopmentalsyndromes.Thesetendto andN-andC-terminalextensions.Alphacrystallinsare resultfrommutationsingenesencodingtranscriptional composedoftwogeneproducts:alpha-Aandalpha-B,for activators,andmostofthesehavebeenidentifiedby acidicandbasic,respectively.Alphacrystallinscanbe sequencingcandidategenesinpatientswithdevelopmental inducedbyheatshockandaremembersofthesmallheat anomalies.Anotableexceptionisthe B-crystallingene, shockprotein (sHSPalsoknownastheHSP20)family. 琢 CRYAB,whichiswidelyexpressedinvarioustissues, Theyactasmolecularchaperonesalthoughtheydonot especiallymuscle.MutationsinCRYABcancausea renatureproteinsandreleasetheminthefashionofatrue spectrumofabnormalitiesrangingfromisolatedcataractsto chaperone;instead theyholdthemin largesoluble mildcataractsassociatedwith myopathy.Asecond aggregates.Post-translationalmodificationsdecreasethe counterexampleistheferritingene,whichcausesthe abilityto chaperone.Theseheterogeneous aggregates hyperferritinemia-cataractsyndrome(Table1)[1,16,17]. consistof30-40subunits; -Aand -Bsubunitshavea3:1 琢 琢 Crystallinproteins Threemajorclassesofubiquitous ratio,respectively.Twoadditionalfunctionsofalpha crystallinsarefoundinthevertebrateeyelens.Inthe crystallinsareanautokinaseactivityandparticipationinthe molecular structureofcrystallinproteins,thereare intracellulararchitecture.Alpha-Aand -Bgeneproducts 琢 -crystallinprotein(40%), -crystallinprotein(35%)and aredifferentiallyexpressed; -Aispreferentiallyrestricted 琢 茁 琢 -crystallinprotein(25%).Theratioofthecrystalinprotein tothelensand -Bisexpressedwidelyinmanytissuesand 酌 琢 compositionanditsspatialsequenceinthemaintenanceof organs.Elevatedexpressionof -Bcrystallinoccursin 琢 crystallintransparencyisveryimportant[18-22].Whenthegene manyneurologicaldiseases;amissensemutationcosegregated ismutated,thecrystallinproteinsarenotonlytheabnormal inafamilywithadesmin-relatedmyopathy [21,22]. proteinstructureandaffectit'scloselypacked,butalsoto CRYAA(crystallin, A) 琢 reducethesolubilityofcrystallinproteinstoformopacities. :21;Location:21q22.3 Alpha-crystallinproteins Alpha-crystallinproteinfamily hastwomembers: A-crystallin(CRYAA)and B-crystallin 琢 琢 (CRYAB)genelocatedinthe21q22.3geneandlocatedin CRYAB(crystallin, B) 琢 theCRYAA1lq22.3-q23.1CRYABcoding,respectively [18]. Chromosome:11;Location:11q22.3-q23.1 A-crystallin,asmallheatshockproteinwithchaperone- 琢 likeactivity,formsdynamicmultimericcomplexes.Recently wedescribedthespontaneousgenerationofamutantprotein Beta-crystallin proteins Beta-crystallins,themost (super A-crystallin)byexonduplicationarisenviaexon heterogeneous,differbythepresenceoftheC-terminal 琢 shufflingconfirmingaclassichypothesis[16-18].Comparisonof extension (presentinthebasicgroup,noneintheacidic 425 Epidemiologyandmoleculargeneticsofcongenitalcataracts

Table 1 Mapped human cataracts Chrom Inh MIM CCV (Volkmann) 1p36 AD 115665 CTPP 1p34-p36 AD 116600 FOXE3 NM_012186 1p32 AD 107250, 601094 GJA8 NM_005267 1q21-q25, 2p24 AD,AR 116200 CCNP 2p12 AD 607304 CRYGC NM_020989 2q33-q35 AD 123660, 123680, 601286 CRYGD NM_006891 2q33-q35 AD,AR 115700, 123690 BFSP2 NM_003571 3q22.1 AD 603212 CRYGS NM_017541 3q26.3-qter AD 123730 GCNT2 NM_001491 6p24-p23 AR 110800 EYA1 NM_172060 8q13.3 AD 601653 CAAR 9q13-q22 AR 212500 PITX3 NM_005029 10q25 AD 602669 CRYAB NM_001885 11q23.3-24.2 AD 123590 AQP0 NM_012064 12q12-14.1 AD 601286 GJA3 NM_021954 13q11-13 AD 601885 CHX10 NM_182894 14q24.3 AR 142993 CCSSO 15q21-q22 AD 605728 HSF4 NM_001538 16q21 AD,AR,S 602438 MAF NM_001031804 16q22-q23 AD 177074 CTAA2 17p13 AD 601202 CRYBA3 NM_005208 17q11-q12 AD 600881 CCA1 (Cerulean - blue dot) 17q24, 19q13, 19q13.4 AD,AR 115660 FTL NM_000146 19q13.33 AD LIM2 NM_002316 19q13.4 AR 154045 BFSP1 NM_001195 20p11.23-p12.1 AR 603307 CPP3 20p12-q12 AD 605387 CHMP4B NM_176812 20q11.22 AD 610897 CRYAA NM_000394 21q22.3 AD, AR, Spo radi c 123580 CRYBB2 NM_00496 22q11.2 AD 123620 CRYBB1 NM_001887 22q11.2-q12.1 AD, AR 600929 CRYBB3 NM_004076 22q11.23-q12.1 AR 123630 CRYBA4 NM_001886 22q11.2 AD 123631 CXN Xp22 XL 300457 NHS NM_198270 Xp22.13 XL 300457 Specific mutations are described above the entry for the or locus. The cDNA sequence changes are given in reference to the NCBI sequence identifier in the Locus column. Chrom: chromosomal location, Inh: inheritance pattern, cDNA: changes in the NCBI DNA sequence listed in the Locus column, AA: changes in the sequence, MIM: Mendelian Inheritance in Man reference. Specific mutations identified are listed above the gene. AD: autosomal dominant, AR: autosomal recessive, XL: X-linked, S: sporadic. and loci are shown in bold, while individual mutations and their descriptions are shown in small lettering above group).Beta-crystallinsformaggregatesofdifferentsizes member,ispartofageneclusterwith -A4, -B1,and 茁 茁 andareabletoself-associatetoformdimersortoform -B3.Achain-terminatingmutationwasfoundtocause 茁 heterodimerswithother -crystallins.Thisgene,a acidic type2ceruleancataracts.Themajor -crystallinstructures 茁 茁 茁 groupmember,encodestwoproteins (crystallin, A3and areasfollows. 茁 crystallin, A1)fromasinglemRNA,thelatterproteinis CRYBA1(crystallin, A1) 茁 茁 17ashorterthancrystallin, A3andisgeneratedbyuseof Chromosome:17;Location:17q11.2 茁 analternatetranslationinitiationsite.Deletionofexons3 and4causestheautosomaldominantdiseasezonular cataractwithsuturalopacities.Thisgene,a basicgroup 茁 426 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 4熏晕燥援 4熏 Aug.18, 圆园11 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-83085628 耘皂葬蚤造押陨允韵援圆园园园岳员远猿援糟燥皂 CRYBA2(crystallin, A2) 茁 Chromosome:2;Location:2q34-q36 Gap junction proteins Gapjunctionswerefirst characterizedbyelectronmicroscopyasregionally CRYBB1(crystallin, B1) 茁 specializedstructuresonplasmamembranesofcontacting Chromosome:22;Location:22q11.2;22q12.1 adherentcells.Thesestructureswereshowntoconsistof cell-to-cellchannels.Proteins,calledconnexins,purified fromfractionsofenrichedgapjunctionsfromdifferent CRYBB3(crystallin, B3) tissuesdiffer.Theconnexinsaredesignatedbytheir 茁 Chromosome:22;Location:22q11.23-q12.1 molecularmass.Anothersystemofnomenclaturedivides gapjunctionproteinsinto2categories, and ,according 琢 茁 tosequencesimilaritiesatthenucleotideandaminoacid levels.Forexample,CX43(121014)isdesignatedα -1gap Gama-crystallinproteins Alphaand familiesare 茁 junctionprotein,whereasCX32(GJB1;304040)andCX26 furtherdividedintoacidicandbasicgroups.Sevenprotein arecalled -1and -2gapjunctionproteins,respectively. regionsexistincrystallins:fourhomologousmotifs,a 茁 茁 ThisnomenclatureemphasizesthatCX32andCX26are connectingpeptide,andN-andC-terminalextensions [21,22]. morehomologoustoeachotherthaneitherofthemisto -crystallins areahomogeneousgroup ofhighly 酌 CX43.Gapjunctionproteinsincludethefollowingthree symmetrical,monomericproteinstypically lacking types:1)GJB2(Gapjunction 2),26kDa,Connexin26 connectingpeptidesandterminalextensions.Theyare 茁 (CX26)Genemaplocus:13q11-q12;2)GJB1(Gapjunction differentiallyregulatedafterearlydevelopment. Four -crystallingenes( -Athrough -D)andthreepseudogenes 1)32kDa,Connexin32(CX32)Genemaplocus:Xq13.1; 酌 酌 酌 茁 ( -E, -F, -G)aretandemlyorganizedinagenomic 3)GJA1(Gapjunction 1),43kDa,connexin43(CX43) 酌 酌 酌 琢 segmentasagenecluster.Whetherduetoagingor genemaplocus:20q11. [23] mutationsinspecificgenes, -crystallinshavebeeninvolved Usingthepairedxenopusoocyteassay,Mese 酌 incataractformation. functionallyanalyzed5CX26mutationsassociatedwith CRYGA(crystallin, A) autosomal recessiveneurosensorydeafness(DFNB1A; 酌 220290).Threeofthemutantswereunabletoform Chromosome:2;Location:2q33-q35 functionalchannels;theother2didelectricallycouplecells, buttheirvoltagegatingpropertiesweredifferentfromwild typeCX26channels.ThedeafnessassociatedwithCX26 CRYGB(crystallin, B) 酌 mutationsiscausednotonlybyreduced potassium Chromosome:2;Location:2q33-q35 recirculationintheinnerear,butalsobyabnormalitiesin theexchangeofothermetabolitesthroughthecochleargap[23]. Elias [24] showedthatthegapjunctionsubunitsCX26 CRYGC(crystallin, C) andCX43(121014)areexpressedatthecontactpoints 酌 Chromosome:2;Location:2q33-q35 betweenradialfibersandmigratingneurons,andthatacute downregulationofCX26orCX43impairsthemigrationof neuronstothecorticalplate.Unexpectedly,gapjunctionsdo notmediateneuronalmigrationbyactingintheclassical CRYGD(crystallin, D) 酌 mannerto provideanaqueous channelforcell-cell Chromosome:2;Location:2q33-q35 communication.Instead,gapjunctionsprovidedynamic adhesivecontactsthatinteractwiththeinternalcytoskeleton toenableleadingprocessstabilizationalongradialfibersas CRYGE(crystallin, E)[Musmusculus] wellasthesubsequenttranslocationofthenucleus.Thegap 酌 Chromosome:1;Location:1C2;132.0cM junctionadhesionsarenecessaryforglial-guidedneuronal migration[24]. Membraneproteins Lensisanon-vasculartissue;thevast CRYGF(crystallin, G) majorityoflenscellsrelyonglycolysistomeetenergy 酌 Chromosome:1;Location:1C3;132.0cM supply.Locatedinthecenterofthelensfiberrelyon 427 Epidemiologyandmoleculargeneticsofcongenitalcataracts passivediffusiontoacceptlessthanadequatenutrition,and peptide,theNPAmotifandasecondandusuallynarrower byspecialtransporttoprovidethenutrientsandthe constrictionknownas'selectivityfilter'orar/Rselectivity metabolicproductsshippedtothelenssurface. filter.Aquaporinsformtetramersinthecellmembrane,with Amembraneproteinisaproteinmoleculethatisattached eachmonomeractingasawaterchannel.Thedifferent to,orassociatedwiththemembraneofacelloran aquaporinscontaindifferencesintheirpeptidesequence, organelle.Morethanhalfofallproteinsinteractwith whichallowsforthesizeoftheporeintheproteintodiffer membranes. Biologicalmembranes consistofa betweenaquaporins.Theresultantsizeoftheporedirectly phospholipid bilayer andavarietyofproteinsthat affectswhatmoleculesareabletopassthroughthepore, accomplishvitalbiologicalfunctions.1)Structuralproteins withsmallporesizesonlyallowingsmallmoleculeslike areattachedtomicrofilamentsinthecytoskeletonwhich watertopassthroughthepore [26,27].Micehomozygousfor ensuresstabilityofthecell;2)Celladhesionmolecules inactivatingmutationsintheaquaporin-0genedevelop allowcellstoidentifyeachotherandinteract.Suchproteins congenitalcataracts[28]. areinvolvedin immuneresponse, forexample;3) Majorintrinsicprotein(MIP)isamemberofthe Membrane produceavarietyof substances water-transportingaquaporinsaswellastheoriginal essentialforcellfunction;4)Membranereceptorproteins memberoftheMIPfamilyofchannelproteins.Thefunction serveasconnectionbetweenthecell'sinternalandexternal ofthefibercellmembraneproteinencodedbythisgeneis environments;5)Transportproteinsplayanimportantrole undetermined,yetthisproteinisspeculatedtoplayarolein inthemaintenanceofconcentrationsof ions.These intracellularcommunication.TheMIPproteinisexpressed transportproteinscomeintwoforms:carrierproteinsand intheocularlensandisrequiredforcorrectlensfunction. channelproteins. MIP(Majorintrinsicprotein) Thestructuresofmembraneproteinsarestabilizedbyweak Chromosome:12;Location:12q13 interactionsandinfluencedbyadditionalinteractionswith thesolubilizingenvironment.The influenceofthe environmentonmembraneproteinstructuresisespecially Lensintrinsicmembraneprotein2 Thisgeneencodes significant.Despitethesignificantfunctionalimportanceof aneyelens-specificprotein(19kDa)foundatthejunctions membraneproteins,the structuralbiologyhasbeen oflensfibercells,whereitmaycontributetocelljunctional particularlychallengingasshownbythelownumberof organization.Itactsasareceptorforcalmodulin,andmay membraneproteinstructuresdetermined.Integralmembrane playanimportantroleinbothlensdevelopmentand proteinsarepresentinaheterogeneousenvironmentthat cataractogenesis.Mutationsinthis genehavebeen posesmajorobstaclesforexistingstructuralmethodologies. associatedwithcataractformation.Alternativelyspliced Aquaporinproteins Aquaporinsareproteinsembeddedin transcriptvariantsencodingdifferentisoformshavebeen thecellmembranethatregulatetheflowofwater. foundforthisgene. Aquaporinsareintegralmembraneproteinsfromalarger LIM2(Lensintrinsicmembraneprotein2) familyofmajorintrinsicproteins(MIP)thatformporesin Chromosome:19;Location:19q13.4 themembraneofbiologicalcells [25].Aquaporinproteinsare madeupofsixtransmembrane -helicesarrangedina 琢 right-handedbundle,withtheaminoandthecarboxyl Beadedfilamentstructuralprotein2 Frameofthelens terminilocatedonthecytoplasmicsurfaceofthemembrane. cellsandthecytoplasmbythecytoskeletoninthelens Theaminoandcarboxylhalvesofthesequenceshow proteininteractionsdetermined.Fibrin-likebeads(beaded similaritytoeachother,inwhatappearstobeatandem filamentstructuralprotein2,BFSP2)istheonlykindof repeat.Someresearchersbelievethatthisresultsfroman expression onlyintheeyesofcytoskeletal proteins earlyevolutioneventthatsawtheduplicationofthe (cytoskeletalprotein)structure. half-sizegene.Therearealsofiveinterhelicalloopregions Morethan99%ofthevertebrateocularlensiscomprisedof (A-E)thatformtheextracellularandcytoplasmicvestibules. terminallydifferentiatedlensfibercells.Twolens-specific LoopsBandEarehydrophobicloopsthatcontainthe intermediatefilament-likeproteins,theproteinproductof highly,althoughnotcompletelyconserved,asparagine- thisgene(phakinin),andfilensin,areexpressedonlyafter proline-alanine (NPA)motif,whichoverlapthemiddleof fibercelldifferentiationhasbegun.Bothproteinsarefound thelipidbilayerofthemembraneforminga3-D'hourglass' inastructurallyuniquecytoskeletalelementthatisreferred structurewherethewaterflowsthrough.Thisoverlapforms toasthebeadedfilament(BF).Mutationsinthisgenehave oneofthetwowell-knownchannelconstrictionsitesinthe beenassociatedwithjuvenile-onset,progressivecataracts 428 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 4熏晕燥援 4熏 Aug.18, 圆园11 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-83085628 耘皂葬蚤造押陨允韵援圆园园园岳员远猿援糟燥皂 andDowling-Mearaepidermolysisbullosasimplex[29]. siteandbindingpartner,theencodedproteincanbea BFSP2(Beadedfilamentstructuralprotein2) transcriptionalactivatororrepressor.Thisproteinplaysa Chromosome:3;Location:3q22.1 roleintheregulationofseveralcellularprocesses,including embryoniclensfibercelldevelopment,increasedT-cell susceptibilitytoapoptosis, andchondrocyteterminal differentiation.Defectsinthis geneareacauseof Transcription factors Transcriptionfactorhasan juvenile-onsetpulverulentcataractaswellascongenital importantroleinembryonicdevelopmentofeye,mutations ceruleancataract4(CCA4).Twotranscriptvariantsencoding inthesegenesoftenbecauseeyehypoplasiasyndrome,these differentisoformshavebeenfoundforthisgene[31-33]. genesistostudytheimportanceofeyehypoplasiasyndrome MAF(v-mafmusculoaponeuroticfibrosarcoma) candidategenes. Antibody-dependentcell-mediated cytotoxicity (ADCC)associatedwiththeoccurrenceof Chromosome:16;Location:16q22-q23 transcriptionfactorgenes,includingheatshocktranscription factor4gene (HSF4),MAF(v-mafmusculoaponeurotic fibrosarcomaoncogenehomolog),pituitaryhomeoboxgene Paired-like homeodomain 3 Thisgeneencodesa 3(PITX3),pairedhomeoboxcontaininggene6(PAX6)and memberoftheRIEG/PITXhomeoboxfamily,whichisin soon. thebicoidclassofhomeodomainproteins.Membersofthis Heat shock 4 Heatshock familyactastranscriptionfactors.Thisproteinisinvolved transcriptionfactors(HSFs)activateheat-shockresponse inlensformationduringeyedevelopment.Mutationsofthis genesunderconditionsofheatorotherstresses.HSF4lacks gene havebeenassociatedwith anteriorsegment thecarboxyl-terminalhydrophobicrepeatwhichisshared mesenchymaldysgenesisandcongenitalcataracts[32,33]. amongallvertebrateHSFsandhasbeensuggestedtobe PITX3(Paired-likehomeodomain3) involvedinthenegativeregulationofDNAbindingactivity. Chromosome:10;Location:10q25 Two alternativelyspliced transcriptsencodingdistinct isoformsandpossessingdifferenttranscriptionalactivity havebeendescribed. Pairedboxgene6 Thisgeneencodespairedboxgene6, HSF4(Heatshocktranscriptionfactor4) oneofmanyhumanhomologsoftheDrosophila Chromosome:16;Location:16q21 melanogastergeneprd.Inadditiontothehallmarkfeature ofthisgenefamily,aconservedpairedboxdomain,the encodedproteinalsocontainsahomeoboxdomain.Both v-mafmusculoaponeuroticfibrosarcoma Muchofour domainsareknowntobindDNA,andfunctionasregulators knowledgeabouttheunderlyingmechanismsof ofgenetranscription.Thisgeneisexpressedinthe cataractogenesishascomefromthegeneticanalysisof developingnervoussystem,andin developingeyes. affectedfamilies:therearecontributionsfromgenescoding Mutationsinthisgeneareknowntocauseoculardisorders fortranscriptionfactors(suchasMAF,PITX3,FoxE3)and suchasaniridiaandPeter'sanomaly.Alternativelyspliced structuralproteinssuchascrystallinsorconnexins [30].In transcriptvariantsencodingeitherthesameordifferent addition,therearecontributionsfromenzymesaffecting isoformhavebeenfoundforthisgene.Mutationsassociated sugarpathways(particularlythegalactosepathway)and withcongenitalcataractsform40,ofwhichonly1speciesis fromaquiteunexpectedarea:axonguidancemoleculeslike causedbymutationsinthepathogenesisoftheindependent ephrinsandtheirreceptors.Cataractousmouselensescanbe occurrenceofADCC(G18W),themutationinterferingwith identifiedeasilybyvisualinspection,andaremarkable thetargetgenePAX6binding,andreduceitstranscriptional numberofmutantlineshavenowbeencharacterized. activationfunctionlocatedinthe1lp13.AnovelPAX6gene Generally,mostofthemousemutantsshowasimilar mutationwasidentifiedinaChineseaniridiafamily.This phenotypetotheirhumancounterparts;however,thereare mutationmayalsocontributetocongenitalcataractsinthese someremarkabledifferences.Itshouldbenotedthatmany aniridiapatients[33-35]. mutationsaffectgenesthatareexpressednotonlyinthe PAX6(Pairedboxgene6) lens,butalsointissuesandorgansoutsidetheeye[31-33]. Chromosome:11;Location:11p13 TheproteinencodedbythisgeneisaDNA-binding,-containingtranscriptionfactorthatactsas a homodimerorasaheterodimer.Dependingonthebinding 429 Epidemiologyandmoleculargeneticsofcongenitalcataracts Ferritinlightchains Whyferritinconcentrationcanlead cataractsareconstantlydiscovered.Studiessuggestthat tocataracts,itisnotclear.Studiessuggestthatferritinfor thereisno morethan12diseasegenesidentified cataractmaybetwofactors:first,ferritinlightchainand chromosomalregionsassociatedwithcongenitalcataracts, heavychaininthebalanceofthepopulationmakesthefree whichincludelp32,lp36,1pter,2p12,2p24-pter,6p24, ironionsandactiveoxygencontentincreases,damageto 8q13.3,15q21-22,15q22.3-q23.1, 17p12-13,17q24, lensfunction.Second,thecellsincreaseinferritinlevels 20p12-q12andsoon [1,17,39-49]. mayleadtotheaggregationoflensproteins.Thisgene SUMMARY encodesthelightsubunitoftheferritinprotein.Ferritinis Thehereditarycongenitalcataractsprovidessomeinsight themajorintracellularironstorageproteininprokaryotes intothosebiologicalsystemsmostimportantfordeveloping andeukaryotes.Itiscomposedof24subunitsoftheheavy andmaintaininglenstransparency,oratleastthosewhich andlightferritinchains.Variationinferritinsubunit aremosteasilydisruptedinaboveoverview.Althoughthe compositionmayaffecttheratesofironuptakeandrelease normallensandcataractinclinicalmolecularbiologymore indifferenttissues.Amajorfunctionofferritinisthe completedescriptionisbeyondthescopeofthereview, storageofironinasolubleandnontoxicstate.Defectsin moredetailedreviewsareavailable [48-53].Otherimportant thislightchainferritingeneareassociatedwithseveral functionalsystemsinclude cytoskeletalandmembrane neurodegenerativediseasesandhyperferritinemia-cataract proteins,especiallythoselimitedtoorfavoredinthelens. syndrome.Thisgenehasmultiplepseudogenes[36]. Assuggestedbytheirhighexpressionlevelsinthelens,the ThemutationobservedinFTLinthisfamilyhighlightsthe crystallinsarethemostcommongroupofproteinsmutated phenotypicheterogeneityofthedisorderinrelationtothe ininheritedcongenitalcataracts.Growthanddifferentiation genotypeastheidenticalmutation(32G>A)haspreviously factorsalsofrequentlyareseencausingcongenitalcataracts, beenreportedintwoItalianfamilieswithentirelydifferent ofteninassociationwithotherfindingsintheir phenotypes.Itisalsothefirstreportof hereditary developmentalspectra[54].Finally,avariedgroupofproteins hyperferritinemia-cataractsyndromeinafamilyofIndian canalsocausecongenitalcataracts.Togetherthesestudies origin[37]. provideinsightsintolensbiologyeasilyaccessibleinno FTL(Ferritinlightchain) otherway.Theycanalsobeofdirectclinicalbenefitin Chromosome:19;Location:19q13.33 somefamilies [55].Inaddition,whilethepathophysiologyof congenitalandhereditarycataractsdiffersinfundamental waysfromthatofagerelatedcataracts,thestudyof Fibroblastgrowthfactors Theproteinencodedbythis congenitalcataractscanprovide insightsintothe geneisamemberofthefibroblastgrowthfactor(FGF) mechanismsoflenstransparencyandtosomeofthewaysin family.FGFfamilymemberspossessbroadmitogenicand whichitcanbelostasthelensages[53-56]. cellsurvivalactivities,andareinvolvedinavarietyof Congenitalcataractisparticularlyseriousbecauseithasthe biologicalprocesses,includingembryonicdevelopment,cell potentialforinhibitingvisualdevelopment,resultingin growth,morphogenesis,tissuerepair,tumorgrowthand permanentblindness.Inheritedcataractsrepresentamajor invasion.Thisproteinisapotentepithelialcell-specific contributiontocongenitalcataracts,especiallyindeveloped growthfactor,whosemitogenicactivityispredominantly countries.Whilecataractrepresentsacommonendstageof exhibitedinkeratinocytesbut notinfibroblastsand mutationsinapotentiallylargenumberofgenesacting endothelialcells.Studiesofmouseandrathomologsofthis throughvariedmechanismsinpracticemostinherited geneimplicatedrolesinmorphogenesisofepithelium, cataractshavebeenassociatedwithasubgroupofgenes reepithelializationofwounds,hairdevelopmentandearly encoding proteinsofparticular importanceforthe lungorganogenesis[38].Usinglinkageanalysis,Swaroop maintenanceoflenstransparencyandhomeostasis [57].The [39] believedthatitmaybefibroblastgrowthfactor7 increasingavailabilityofmoredetailedinformationabout (FGF7) gene mutation associatedwithcongenital theseproteinsandtheirfunctionsandismakingitpossible cataract-related. tounderstandthepathophysiologyofcataractsandthe FGF7(fibroblastgrowthfactor7) biologyofthelensingeneral. Chromosome:15;Location:15q21.2 REFERENCES 1HejtmancikJF.Congenitalcataractsandtheirmoleculargenetics. 2008;19(2):134-149 2KuszakJR,ZoltoskiRK,SivertsonC.Fibrecellorganizationincrystalline lenses. 2004;78(3):673-687 Otherproteins Thenewgenesthatcausecongenital 3HaargaardB,WohlfahrtJ,FledeliusHC,RosenbergT,MelbyeM.Anationwide 430 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 4熏晕燥援 4熏 Aug.18, 圆园11 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-83085628 耘皂葬蚤造押陨允韵援圆园园园岳员远猿援糟燥皂 Danishstudyof1027casesofcongenital/infantilecataracts:etiologicalandclinical 26GonenT,WalzT.Thestructureofaquaporins. 2006;39(4): classifications. 2004;111(12):2292-2298 361-396 4JoharSR,SavaliaNK,VasavadaAR,GuptaPD.Epidemiologybasedetiological 27ChepelinskyAB.StructuralfunctionofMIP/aquaporin0intheeyelens;genetic studyofpediatriccataractinwesternIndia. 2004;58(3):115-121 defectsleadtocongenitalinheritedcataracts. 2009;??(190): 5HeijlA,LeskeMC.Cataractepidemiology. 2007;114(1):201 265-297 6ChandrasekaranS,CummingRG,RochtchinaE,MitchellP.Associations 28OkamuraT,MiyoshiI,TakahashiK,MototaniY,IshigakiS,KonY,KasaiN. betweenelevatedintraocularpressureandglaucoma,useofglaucomamedications, Bilateralcongenitalcataractsresultfromagain-of-functionmutationinthegene and5-yearincidentcataract:theBlueMountainsEyeStudy. foraquaporin-0inmice. 2003;81(4):361-368 2006;113(3):417-424 29MaX,LiFF,WangSZ,GaoC,ZhangM,ZhuSQ.AnewmutationinBFSP2 7WestS.Epidemiologyofcataract:accomplishmentsover25yearsandfuture (G1091A)causesautosomaldominantcongenitallamellarcataracts. directions. 2007;14(4):173-178 2008;14:1906-1911 8FosterA,GilbertC,RahiJ.Epidemiologyofcataractinchildhood:aglobal 30ChurchillA,GrawJ.Clinicalandexperimentaladvancesincongenitaland perspective. 1997;23(Suppl1):601-604 paediatriccataracts. 2011;366(1568): 9VajpayeeRB,JoshiS,SaxenaR,GuptaSK.EpidemiologyofcataractinIndia: 1234-1249 combatingplansandstrategies. 1999;31(2):86-92 31BerryV,FrancisPJ,PrescottQ,WaseemNH,MooreAT,BhattacharyaSS.A 10McCartyCA,MukeshBN,FuCL,TaylorHR.Theepidemiologyofcataractin novel1-bpdeletioninPITX3causingcongenitalposteriorpolarcataract. 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46YamadaK,TomitaHA,KanazawaS,MeraA,AmemiyaT,NiikawaN. 52McKayJD,PattersonB,CraigJE,Russell-EggittIM,WirthMG,BurdonKP, Geneticallydistinctautosomaldominantposteriorpolarcataractina HewittAW,CohnAC,KerdraonY,MackeyDA.Thetelomereofhuman four-generationJapanesefamily. 2000;129(2):159-165 chromosome1pcontainsatleasttwoindependentautosomaldominantcongenital 47IonidesAC,BerryV,MackayDS,MooreAT,BhattacharyaSS,ShielsA.A cataractgenes. 2005;89(7):831-834 locusforautosomaldominantposteriorpolarcataractonchromosome1p. 53HejtmancikJF,PiatigorskyJ.LensProteinsandtheirMolecularBiology.In: 1997;6(1):47-51 AlpertDM,JakobiecFA,AzarDT,GragoudasES,editors. 48KramerP,YountJ,MitchellT,LaMorticellaD,Carrero-ValenzuelaR,Lovrien .W.B.SaundersCo.;Philadelphia,2000:1409-1428 E,MaumeneeI,LittM.Asecondgeneforceruleancataractsmapstothebeta 54HejtmancikJF,DatilesM.CongenitalandInheritedCataracts.In:TasmanW, crystallinregiononchromosome22. 1996;35(3):539-542 JaegerEA,editors. LippincottWillliamsand 49PadmaT,AyyagariR,MurtyJS,BastiS,FletcherT,RaoGN,Kaiser-Kupfer Wilkins;Philadelphia,2001:1-22 M,HejtmancikJF.Autosomaldominantzonularcataractwithsuturalopacities 55RechesA,YaronY,BurdonK,Crystal-ShalitO,KidronD,MalcovM,Tepper localizedtochromosome17q11-12. 1995;57(4):840-845 R.Prenataldetectionofcongenitalbilateralcataractleadingtothediagnosisof 50StambolianD,AiY,SidjaninD,NesburnK,SatheG,RosenbergM,Bergsma Nance-Horansyndromeintheextendedfamily. 2007;27:662-664 DJ.CloningofthegalactokinasecDNAandidentificationofmutationsintwo 56FinziS,LiY,MitchellTN,FarrA,MaumeneeIH,SallumJM,SundinO. familieswithcataracts. 1995;10(3):307-312 Posteriorpolarcataract:geneticanalysisofalargefamily. 51EibergH,LundAM,WarburgM,RosenbergT.Assignmentofcongenital 2005;26(3):125-130 cataractVolkmanntype(CCV)tochromosome1p36. 1995;96(1): 57Medina-MartinezO,JamrichM.Foxeviewoflensdevelopmentanddisease. 33-38 2007;134(8):1455-1463

TeachingCoursesin2012

1TEACHINGCOURSE withInternationalFacultyon: retinalANDVITREOUSSurgery MinimalExtraocularSurgeryforRetinalDetachmentandProphylaxisoftheFellowEye AbuDhabi,UNITEDARABEMIRATES DuringJointMeetingofWOC2012,XXXIIIICO2012, 12th InternationalCongressofMEACO2012 February16-20,2012 Organization: Prof.Dr.IngridKreissig,MD, Dept.ofOphthalmology,Univ.ofMannheim-Heidelberg,68167Mannheim,Germany; Website:http://kreissig.uni-hd.de/ E-mail:[email protected] LocalOrganization:website:www.WOC2012.org/

2TEACHINGCOURSE withInternationalFacultyon: retinalANDVITREOUSSurgery Khartoum,SUDAN,Febr.23-24,2012 Organization: Prof.Dr.IngridKreissig,MD, Dept.ofOphthalmology,Univ.ofMannheim-Heidelberg,69167Mannheim,Germany Website:http://kreissig.uni-hd.de/ E-mail:[email protected] SudaneseOphthalmologicalSociety,Khartoum,Sudan E-mail:[email protected]

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