[1]王珏雪,万修华.先天性白内障晶状体蛋白致病基因及其功能研究进展[J].眼科新进展,2023,43(8):656-661.[doi:10.13389/j.cnki.rao.2023.0133]
　WANG Juexue,WAN Xiuhua.Research progress of pathogenic crystallin genes on congenital cataract and their functions[J].Recent Advances in Ophthalmology,2023,43(8):656-661.[doi:10.13389/j.cnki.rao.2023.0133]
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先天性白内障晶状体蛋白致病基因及其功能研究进展/HTML
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《眼科新进展》[ISSN:1003-5141/CN:41-1105/R]

卷:
43卷
期数:
2023年8期
页码:
656-661
栏目:
文献综述
出版日期:
2023-08-05

文章信息/Info

Title:
Research progress of pathogenic crystallin genes on congenital cataract and their functions
作者:
王珏雪; 万修华
100010　北京市,首都医科大学附属北京同仁医院
Author(s):
WANG Juexue; WAN Xiuhua
Beijing Tongren Eye Center,Beijing Tongren Hospital of Capital Medical University，Beijing 100010，China
关键词:
先天性白内障; 晶状体蛋白; 基因突变
Keywords:
congenital cataract;  crystallin;  gene mutation
分类号:
R776.1
DOI:
10.13389/j.cnki.rao.2023.0133
文献标志码:
A
摘要:
先天性白内障病因复杂，遗传性因素占22.3%。晶状体蛋白基因占突变基因的50.0%，包括α-晶状体蛋白、β-晶状体蛋白、γ-晶状体蛋白，其突变的致病机制主要是通过改变蛋白的二级或三级结构干扰蛋白质正确折叠方式从而影响蛋白的溶解度和稳定性，并形成细胞毒性的聚集小体；干扰蛋白与蛋白之间的相互作用并诱导细胞凋亡；消除三磷酸腺苷拮抗聚集效应等，目前针对致病机制的初步药物研究有羊毛甾醇等，可为治疗白内障提供新思路。因此，本文就晶状体蛋白基因的突变及其功能研究进行综述。
Abstract:
The pathogenesis of congenital cataracts is complex; genetic factors account for 22.3%. The crystallin genes account for half of the mutant genes, including α-crystallin, β-crystallin and γ-crystallin. Its pathogenic mechanism is mainly to change the secondary or tertiary structure of the protein to interfere with the correct folding of the protein, thereby affecting the protein solubility and stability, forming cytotoxic aggregates, interfering with protein-protein interaction and inducing apoptosis. Besides, it can eliminate the antagonistic aggregation effect of adenosine triphosphate. At present, lanosterol and other drugs have been used for the preliminary study on the pathogenesis of congenital cataracts, providing new ideas for the treatment of cataracts. Therefore, the mutations and functions of crystallin genes are reviewed in this paper.

参考文献/References:

［1］　SHEELADEVI S,LAWRENSON J G,FIELDER A R,SUTTLE C M.Global prevalence of childhood cataract:a systematic review［J］.Eye (Lond),2016,30(9):1160-1169.
［2］　WU X,LONG E,LIN H,LIU Y.Prevalence and epidemiological characteristics of congenital cataract:a systematic review and meta-analysis［J］.Sci Rep,2016,6:28564.
［3］　BREMOND-GIGNAC D,DARUICH A,ROBERT M P,VALLEIX S.Recent developments in the management of congenital cataract［J］.Ann Transl Med,2020,8(22):1545.
［4］　BERRY V,IONIDES A,PONTIKOS N,MOORE A T,QUINLAN R A,MICHAELIDES M.Variants in PAX6,PITX3 and HSF4 causing autosomal dominant congenital cataracts［J］.Eye (Lond),2021,36(8):1694-1701.
［5］　REIS L M,SEMINA E V.Genetic landscape of isolated pediatric cataracts:extreme heterogeneity and variable inheritance patterns within genes［J］.Hum Genet,2019,138(8-9):847-863.
［6］　LI J,CHEN X,YAN Y,YAO K.Molecular genetics of congenital cataracts［J］.Exp Eye Res,2020,191:107872.
［7］　GHOSH K S,CHAUHAN P.Crystallins and their complexes［J］.Subcell Biochem,2019,93:439-460.
［8］　TAKEMOTO L,PONCE A,SORENSEN C M.Age-dependent association of gamma-crystallins with aged alpha-crystallins from old bovine lens［J］.Mol Vis,2008,14:970-974.
［9］　GRAW J.Genetics of crystallins:cataract and beyond［J］.Exp Eye Res,2009,88(2):173-189.
［10］　MOREAU K L,KING J A.Protein misfolding and aggregation in cataract disease and prospects for prevention［J］.Trends Mol Med,2012,18(5):273-282.
［11］　LITT M,KRAMER P,LAMORTICELLA D M,MURPHEY W,LOVRIEN E W,WELEBER R G.Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA［J］.Hum Mol Genet,1998,7(3):471-474.
［12］　DEVI R R,YAO W,VIJAYALAKSHMI P,SERGEEV Y V,SUNDARESAN P,HEJTMANCIK J F.Crystallin gene mutations in Indian families with inherited pediatric cataract［J］.Mol Vis,2008,14:1157-1170.
［13］　KHAN A O,ALDAHMESH M A,MEYER B.Recessive congenital total cataract with microcornea and heterozygote carrier signs caused by a novel missense CRYAA mutation (R54C)［J］.Am J Ophthalmol,2007,144(6):949-952.
［14］　KHOSHAMAN K,YOUSEFI R,TAMADDON A M,ABOLMAALI S S,ORYAN A,MOOSAVI-MOVAHEDI A A,et al.The impact of different mutations at Arg54 on structure,chaperone-like activity and oligomerization state of human αA-crystallin:the pathomechanism underlying congenital cataract-causing mutations R54L,R54P and R54C［J］.Biochim Biophys Acta Proteins Proteom,2017,1865(5):604-618.
［15］　BHAGYALAXMI S G,SRINIVAS P,BARTON K A,KUMAR K R,VIDYAVATHI M,PETRASH J M,et al.A novel mutation (F71L) in alphaA-crystallin with defective chaperone-like function associated with age-related cataract［J］.Biochim Biophys Acta,2009,1792(10):974-981.
［16］　KORE R,HEDGES R A,OONTHONPAN L,SANTHOSHKUMAR P,SHARMA K K,ABRAHAM E C.Quaternary structural parameters of the congenital cataract causing mutants of αA-crystallin［J］.Mol Cell Biochem,2012,362(1-2):93-102.
［17］　SINGH D,RAMAN B,RAMAKRISHNA T,RAO CH M.The cataract-causing mutation G98R in human alphaA-crystallin leads to folding defects and loss of chaperone activity［J］.Mol Vis,2006,12:1372-1379.
［18］　AHSAN S M,BAKTHISARAN R,TANGIRALA R,RAO C M.Nucleosomal association and altered interactome underlie the mechanism of cataract caused by the R54C mutation of αA-crystallin［J］.Biochim Biophys Acta Gen Subj,2021,1865(5):129846.
［19］　FRANKFATER C,BOZEMAN S L,HSU F F,ANDLEY U P.Alpha-crystallin mutations alter lens metabolites in mouse models of human cataracts［J］.PLoS One,2020,15(8):e0238081.
［20］　LI L,FAN D B,ZHAO Y T,LI Y,KONG D Q,CAI F F,et al.Two novel mutations identified in ADCC families impair crystallin protein distribution and induce apoptosis in human lens epithelial cells［J］.Sci Rep,2017,7(1):17848.
［21］　BOVA M P,YARON O,HUANG Q,DING L,HALEY D A,STEWART P L,et al.Mutation R120G in alphaB-crystallin,which is linked to a desmin-related myopathy,results in an irregular structure and defective chaperone-like function［J］.Proc Natl Acad Sci U S A,1999,96(11):6137-6142.
［22］　LIU Y,ZHANG X,LUO L,WU M,ZENG R,CHENG G,et al.A novel alphaB-crystallin mutation associated with autosomal dominant congenital lamellar cataract［J］.Invest Ophthalmol Visual Sci,2006,47(3):1069-1075.
［23］　FICHNA J P,POTULSKA-CHROMIK A,MISZTA P,REDOWICZ M J,KAMINSKA A M,ZEKANOWSKI C,et al.A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects αB-crystallin structure［J］.BBA Clin,2017,7:1-7.
［24］　LI H,LI C,LU Q,SU T,KE T,LI D W,et al.Cataract mutation P20S of alphaB-crystallin impairs chaperone activity of alphaA-crystallin and induces apoptosis of human lens epithelial cells［J］.Biochim Biophys Acta,2008,1782(5):303-309.
［25］　HAYES V H,DEVLIN G,QUINLAN R A.Truncation of alphaB-crystallin by the myopathy-causing Q151X mutation significantly destabilizes the protein leading to aggregate formation in transfected cells［J］.J Biol Chem,2008,283(16):10500-10512.
［26］　ADHIKARI A S,SINGH B N,RAO K S,RAO C M.αB-crystallin,a small heat shock protein,modulates NF-κB activity in a phosphorylation-dependent manner and protects muscle myoblasts from TNF-α induced cytotoxicity［J］.Biochim Biophy Acta,2011,1813(8):1532-1542.
［27］　FUJITA Y,OHTO E,KATAYAMA E,ATOMI Y.AlphaB-Crystallin-coated MAP microtubule resists nocodazole and calcium-induced disassembly［J］.J Cell Sci,2004,117(Pt9):1719-1726.
［28］　SINGH B N,RAO K S,RAMAKRISHNA T,RANGARAJ N,RAO CH M.Association of alphaB-crystallin,a small heat shock protein,with actin:role in modulating actin filament dynamics in vivo［J］.J Mol Biol,2007,366(3):756-767.
［29］　RAJU I,ABRAHAM E C.Mutants of human αB-crystallin cause enhanced protein aggregation and apoptosis in mammalian cells:influence of co-expression of HspB1［J］.Biochem Biophys Res Commun,2013,430(1):107-112.
［30］　XIA X Y,WU Q Y,AN L M,LI W W,LI N,LI T F,et al.A novel P20R mutation in the alpha-B crystallin gene causes autosomal dominant congenital posterior polar cataracts in a Chinese family［J］.BMC Ophthalmol,2014,14:108.
［31］　JIAO X,KHAN S Y,IRUM B,KHAN A O,WANG Q,KABIR F,et al.Missense mutations in CRYAB are liable for recessive congenital cataracts［J］.PLoS One,2015,10(9):e0137973.
［32］　WU M H,YU Y H,HAO Q L,GONG X H,YAO K.A novel splice site mutation of CRYBA3/A1 gene associated with congenital cataract in a Chinese family［J］.Int J Ophthalmol,2017,10(1):1-5.
［33］　WANG K J,ZHA X,CHEN D D,ZHU S Q.Mutation analysis of families with autosomal dominant congenital cataract:a recurrent mutation in the CRYBA1/A3 gene causing congenital nuclear cataract［J］.Curr Eye Res,2018,43(3):304-307.
［34］　XU J,WANG H,WU C,WANG A,WU W,XU J,et al.Pathogenic mechanism of congenital cataract caused by the CRYBA1/A3-G91del variant and related intervention strategies［J］.Int J Biol Macromol,2021,189:44-52.
［35］　ZHAO L,CHEN X J,ZHU J,XI Y B,YANG X,HU L D,et al.Lanosterol reverses protein aggregation in cataracts［J］.Nature,2015,523(7562):607-611.
［36］　REIS L M,TYLER R C,MUHEISEN S,RAGGIO V,SALVIATI L,HAN D P,et al.Whole exome sequencing in dominant cataract identifies a new causative factor,CRYBA2,and a variety of novel alleles in known genes［J］.Hum Genet,2013,132(7):761-770.
［37］　RECHSTEINER D,ISSLER L,KOLLER S,LANG E,BHR L,FEIL S,et al.Genetic analysis in a Swiss cohort of bilateral congenital cataract［J］.JAMA Ophthalmol,2021,139(7):691-700.
［38］　ZHAI Y,LI J,YU W,ZHU S,YU Y,WU M,et al.Targeted exome sequencing of congenital cataracts related genes:broadening the mutation spectrum and genotype-phenotype correlations in 27 Chinese han families［J］.Sci Rep,2017,7(1):1219.
［39］　BILLINGSLEY G,SANTHIYA S T,PATERSON A D,OGATA K,WODAK S,HOSSEINI S M,et al.CRYBA4,a novel human cataract gene,is also involved in microphthalmia［J］.Am J Hum Genet,2006,79(4):702-709.
［40］　LI W,JI Q,WEI Z,CHEN Y L,ZHANG Z,YIN X,et al.Biochemical characterization of G64W mutant of acidic beta-crystallin 4［J］.Exp Eye Res,2019,186:107712.
［41］　KUMAR M,AGARWAL T,KAUR P,KUMAR M,KHOKHAR S,DADA R.Molecular and structural analysis of genetic variations in congenital cataract［J］.Mol Vis,2013,19:2436-2450.
［42］　YU Y,QIAO Y,YE Y,LI J,YAO K.Identification and characterization of six β-crystallin gene mutations associated with congenital cataract in Chinese families［J］.Mol Genet Genomic Med,2021,9(3):e1617.
［43］　LI J,LENG Y,HAN S,YAN L,LU C,LUO Y,et al.Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract［J］.Orphanet J Rare Dis,2018,13(1):94.
［44］　CHEN J,WANG Q,CABRERA P E,ZHONG Z,SUN W,JIAO X,et al.Molecular genetic analysis of Pakistani families with autosomal recessive congenital cataracts by homozygosity screening［J］.Invest Ophthalmol Vis Sci,2017,58(4):2207-2217.
［45］　WANG Z,HUANG C,SUN Y,LV H,ZHANG M,LI X.Novel mutations associated with autosomal-dominant congenital cataract identified in Chinese families［J］.Exp Ther Med,2019,18(4):2701-2710.
［46］　MACKAY D S,BOSKOVSKA O B,KNOPF H L,LAMPI K J,SHIELS A.A nonsense mutation in CRYBB1 associated with autosomal dominant cataract linked to human chromosome 22q［J］.Am J Hum Genet,2002,71(5):1216-1221.
［47］　JI Y,ZHAO X,ZHANG J,ZHANG D,TIAN C,ZHANG L,et al.A novel missense mutation of CRYBB1 causes congenital cataract in a Chinese family［J］.Eur J Ophthalmol,2021,31(3):1064-1069.
［48］　BERRY V,IONIDES A,PONTIKOS N,GEORGIOU M,YU J,OCAKA L A,et al.The genetic landscape of crystallins in congenital cataract［J］.Orphanet J Rare Dis,2020,15(1):333.
［49］　RAO Y,DONG S,LI Z,YANG G,PENG C,YAN M,et al.A novel truncation mutation in CRYBB1 associated with autosomal dominant congenital cataract with nystagmus［J］.Mol Vis,2017,23:624-637.
［50］　LENG X Y,LI H Y,WANG J,QI L B,XI Y B,YAN Y B.Congenital microcornea-cataract syndrome-causing mutation X253R increases βB1-crystallin hydrophobicity to promote aggregate formation［J］.Biochem J,2016,473(14):2087-2096.
［51］　ZHAO W J,XU J,CHEN X J,LIU H H,YAO K,YAN Y B.Effects of cataract-causing mutations W59C and W151C on βB2-crystallin structure,stability and folding［J］.Int J Biol Macromol,2017,103:764-770.
［52］　CHEN D,ZHU S.Whole-exome sequencing identification of a recurrent CRYBB2 variant in a four-generation Chinese family with congenital nuclear cataracts［J］.Exp Ther Med,2021,22(6):1375.
［53］　ZIN O A,NEVES L M,MOTTA F L,HOROVITZ D D G,GUIDA L,GOMES L H F,et al.Novel mutation in CRYBB3 causing pediatric cataract and microphthalmia［J］.Genes (Basel),2021,12(7):1069.
［54］　VENDRA V P,KHAN I,CHANDANI S,MUNIYANDI A,BALASUBRAMANIAN D.Gamma crystallins of the human eye lens［J］.Biochim Biophys Acta,2016,1860(1PtB):333-343.
［55］　ZHONG Z,WU Z,HAN L,CHEN J.Novel mutations in CRYGC are associated with congenital cataracts in Chinese families［J］.Sci Rep,2017,7(1):189.
［56］　XI Y B,CHEN X J,ZHAO W J,YAN Y B.Congenital cataract-causing mutation G129C in γC-crystallin promotes the accumulation of two distinct unfolding intermediates that form highly toxic aggregates［J］.J Mol Biol,2015,427(17):2765-2781.
［57］　FU C,XU J,YANG X,CHEN X,YAO K.Cataract-causing mutations L45P and Y46D impair the thermal stability of γC-crystallin［J］.Biochem Biophys Res Commun,2021,539:70-76.
［58］　FU C,XU J,JIA Z,YAO K,CHEN X.Cataract-causing mutations L45P and Y46D promote γC-crystallin aggregation by disturbing hydrogen bonds network in the second greek key motif［J］.Int J Biol Macromol,2021,167:470-478.
［59］　SEREBRYANY E,YU S,TRAUGER S A,BUDNIK B,SHAKHNOVICH E I.Dynamic disulfide exchange in a crystallin protein in the human eye lens promotes cataract-associated aggregation［J］.J Biol Chem,2018,293(46):17997-18009.
［60］　AGUAYO-ORTIZ R,GONZLEZ-NAVEJAS A,PALOMINO-VIZCAINO G,RODRIGUEZ-MEZA O,COSTAS M,QUINTANAR L,et al.Thermodynamic stability of human γD-crystallin mutants using alchemical free-energy calculations［J］.J Phys Chem B,2019,123(27):5671-5677.
［61］　WONG E K,PRYTKOVA V,FREITES J A,BUTTS C T,TOBIAS D J.Molecular mechanism of aggregation of the cataract-related γD-crystallin W42R variant from multiscale atomistic simulations［J］.Biochemistry,2019,58(35):3691-3699.
［62］　BOATZ J C,WHITLEY M J,LI M,GRONENBORN A M,VAN DER WEL P C A.Cataract-associated P23T γD-crystallin retains a native-like fold in amorphous-looking aggregates formed at physiological pH［J］.Nat Commun,2017,8:15137.
［63］　WANG K J,LIAO X Y,LIN K,XI Y B,WANG S,WAN X H,et al.A novel F30S mutation in γS-crystallin causes autosomal dominant congenital nuclear cataract by increasing susceptibility to stresses［J］.Int J Biol Macromol,2021,172:475-482.
［64］　ZHANG T,YAN L,LENG Y,CHEN C,MA L,WANG Q,et al.A novel missense mutation of CRYGS underlies congenital cataract in a Chinese family［J］.Gene,2018,675:9-14.
［65］　YANG X,XU J,FU C,JIA Z,YAO K,CHEN X.The cataract-related S39C variant increases γS-crystallin sensitivity to environmental stress by destroying the intermolecular disulfide cross-links［J］.Biochem Biophys Res Commun,2020,526(2):459-465.
［66］　ZHU S,XI X B,DUAN T L,ZHAI Y,LI J,YAN Y B,et al.The cataract-causing mutation G75V promotes γS-crystallin aggregation by modifying and destabilizing the native structure［J］.Int J Biol Macromol,2018,117:807-814.
［67］　HE Y,KANG J,SONG J.ATP antagonizes the crowding-induced destabilization of the human eye-lens protein γS-crystallin［J］.Biochem Biophys Res Commun,2020,526(4):1112-1117.
［68］　HE Y,KANG J,SONG J.Cataract-causing G18V eliminates the antagonization by ATP against the crowding-induced destabilization of human γS-crystallin［J］.Biochem Biophys Res Commun,2020,530(3):554-560.

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备注/Memo

备注/Memo:
国家自然科学基金项目（编号：82171037）
更新日期/Last Update: 2023-08-05