脆性X相关性疾病研究进展
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摘要
脆性X相关性疾病(FragileXassociatedDisorders,FXD)是由脆性X智力低下蛋白(FragileXMental Retardation Protein,FMRP)部分或完全丧失引起的家族遗传性疾病。其中脆性X综合征(Fragile X syndrome,FXS)是遗传性智力残疾和自闭症的最常见原因之一,其发病率仅次于唐氏综合征,占非特发性智力低下患者的2%-6%,在X连锁智力低下患者中占40%。FXD临床表现不典型,遗传方式多样化。本文将从FXD的临床表现,FMR1基因及其致病机制,FMRP结构及其对转录翻译过程中的影响等方面进行综述。
Fragile X associated Disorders(FXD)are a familial hereditary disease caused by partial or complete loss of Fragile X Mental Retardation Protein(FMRP). Fragile X syndrome(FXS)is the most common cause of hereditary intellectual disability and autism,and is one of the most common hereditary mental retardation diseases. The morbidity is only second to Down′s syndrome,accounting for 2%-6% of non-idiopathic and 40% of X-linked mental retardation patients. The clinical manifestation of FXD is not typical,and the genetic mode is diversified. This article reviews the clinical manifestations of FXD,FMR1 gene and its pathogenesis,FMRP structure and its effect on transcription and translation.
Fragile X associated Disorders(FXD)are a familial hereditary disease caused by partial or complete loss of Fragile X Mental Retardation Protein(FMRP). Fragile X syndrome(FXS)is the most common cause of hereditary intellectual disability and autism,and is one of the most common hereditary mental retardation diseases. The morbidity is only second to Down′s syndrome,accounting for 2%-6% of non-idiopathic and 40% of X-linked mental retardation patients. The clinical manifestation of FXD is not typical,and the genetic mode is diversified. This article reviews the clinical manifestations of FXD,FMR1 gene and its pathogenesis,FMRP structure and its effect on transcription and translation.
引文
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[2]ELTZER M M,BAKER M W,HONG J,et al.Prevalence of CGGexpansions of the FMR1 gene in a US population-based sample[J].Am J Med Genet B Neuropsychiatr Genet,2012,159B(5):589-97.
[3]HUNTER J,RIVERO-ARIAS O,ANGELOV A,et al.Epidemiology of fragile X syndrome:a systematic review and meta-analysis[J].Am J Med Genet A,2014,164A(7):1648-58.
[4]TASSONE F,IONG K P,TONG T H,et al.FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States[J].Genome Med,2012,4(12):100.
[5]PESSO R,BERKENSTADT M,CUCKLE H,et al.Screening for fragile X syndrome in women of reproductive age[J].Prenat Diagn,2000,20(8):611-4.
[6]SALDARRIAGA W,LEIN P,GONZALEZ TESHIMA L Y,et al.Phenobarbital use and neurological problems in FMR1 premutation carriers[J].Neurotoxicology,2016,53(141-7.
[7]WHEELER A C,BAILEY D B,JR.,BERRY-KRAVIS E,et al.Associated features in females with an FMR1 premutation[J].JNeurodev Disord,2014,6(1):30.
[8]HAMLIN A A,SUKHAREV D,CAMPOS L,et al.Hypertension in FMR1 premutation males with and without fragile X-associated tremor/ataxia syndrome(FXTAS)[J].Am J Med Genet A,2012,158A(6):1304-9.
[9]AU J,AKINS R S,BERKOWITZ-SUTHERLAND L,et al.Prevalence and risk of migraine headaches in adult fragile Xpremutation carriers[J].Clin Genet,2013,84(6):546-51.
[10]HAMLIN A,LIU Y,NGUYEN D V,et al.Sleep apnea in fragile X premutation carriers with and without FXTAS[J].Am J Med Genet B Neuropsychiatr Genet,2011,156B(8):923-8.
[11]SUMMERS S M,COGSWELL J,GOODRICH J E,et al.Prevalence of restless legs syndrome and sleep quality in carriers of the fragile X premutation[J].Clin Genet,2014,86(2):181-4.
[12]LEEHEY M A,LEGG W,TASSONE F,et al.Fibromyalgia in fragile X mental retardation 1 gene premutation carriers[J].Rheumatology(Oxford),2011,50(12):2233-6.
[13]COFFEY S M,COOK K,TARTAGLIA N,et al.Expanded clinical phenotype of women with the FMR1 premutation[J].Am JMed Genet A,2008,146A(8):1009-16.
[14]FRANKE P,BARBE B,LEBOYER M,et al.Fragile X syndrome.II.Cognitive and behavioral correlates of mutations of the FMR-1gene[J].Eur Psychiatry,1996,11(5):233-43.
[15]KEYSOR C S,MAZZOCCO M M.A developmental approach to understanding Fragile X syndrome in females[J].Microsc Res Tech,2002,57(3):179-86.
[16]HAGERMAN R J,BERRY-KRAVIS E,HAZLETT H C,et al.Fragile X syndrome[J].Nat Rev Dis Primers,2017,3(17065.
[17]SALDARRIAGA W,TASSONE F,GONZALEZ-TESHIMA LY,et al.Fragile X syndrome[J].Colomb Med(Cali),2014,45(4):190-8.
[18]JACQUEMONT S,FARZIN F,HALL D,et al.Aging in individuals with the FMR1 mutation[J].Am J Ment Retard,2004,109(2):154-64.
[19]HAGERMAN P J,GRECO C M,HAGERMAN R J.A cerebellar tremor/ataxia syndrome among fragile X premutation carriers[J].Cytogenet Genome Res,2003,100(1-4):206-12.
[20]BERRY-KRAVIS E,LEWIN F,WUU J,et al.Tremor and ataxia in fragile X premutation carriers:blinded videotape study[J].Ann Neurol,2003,53(5):616-23.
[21]JACQUEMONT S,HAGERMAN R J,LEEHEY M,et al.Fragile X premutation tremor/ataxia syndrome:molecular,clinical,and neuroimaging correlates[J].Am J Hum Genet,2003,72(4):869-78.
[22]HAGERMAN R,HAGERMAN P.Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome[J].Lancet Neurol,2013,12(8):786-98.
[23]RAJARATNAM A,SHERGILL J,SALCEDO-ARELLANO M,et al.Fragile X syndrome and fragile X-associated disorders[J].F1000Res,2017,6(2112.
[24]BROUWER J R,WILLEMSEN R,OOSTRA B A.The FMR1gene and fragile X-associated tremor/ataxia syndrome[J].Am JMed Genet B Neuropsychiatr Genet,2009,150B(6):782-98.
[25]ASHLEY A E,SHERMAN S L.Population dynamics of a meiotic/mitotic expansion model for the fragile X syndrome[J].Am J Hum Genet,1995,57(6):1414-25.
[26]WOHRLE D,KOTZOT D,HIRST M C,et al.A microdeletion of less than 250 kb,including the proximal part of the FMR-Igene and the fragile-X site,in a male with the clinical phenotype of fragile-X syndrome[J].Am J Hum Genet,1992,51(2):299-306.
[27]TARLETON J,KENNESON A,TAYLOR A K,et al.A single base alteration in the CGG repeat region of FMR1:possible effects on gene expression and phenotype[J].J Med Genet,2002,39(3):196-200.
[28]COLLINS S C,BRAY S M,SUHL J A,et al.Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males[J].Am J Med Genet A,2010,152A(10):2512-20.
[29]GRONSKOV K,BRONDUM-NIELSEN K,DEDIC A,et al.Anonsense mutation in FMR1 causing fragile X syndrome[J].Eur JHum Genet,2011,19(4):489-91.
[30]HAGERMAN R J,HAGERMAN P.Fragile X-associated tremor/ataxia syndrome-features,mechanisms and management[J].Nat Rev Neurol,2016,12(7):403-12.
[31]TASSONE F,HAGERMAN R J,TAYLOR A K,et al.Elevated levels of FMR1 mRNA in carrier males:a new mechanism of involvement in the fragile-X syndrome[J].Am J Hum Genet,2000,66(1):6-15.
[32]TASSONE F,HAGERMAN R J,CHAMBERLAIN W D,et al.Transcription of the FMR1 gene in individuals with fragile Xsyndrome[J].Am J Med Genet,2000,97(3):195-203.
[33]KENNESON A,ZHANG F,HAGEDORN C H,et al.Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers[J].Hum Mol Genet,2001,10(14):1449-54.
[34]TASSONE F,BEILINA A,CAROSI C,et al.Elevated FMR1mRNA in premutation carriers is due to increased transcription[J].RNA,2007,13(4):555-62.
[35]JIN P,ZARNESCU D C,CEMAN S,et al.Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway[J].Nat Neurosci,2004,7(2):113-7.
[36]段现来.脆性X相关疾病FMR1基因突变筛查和致病性分析[D];广州医科大学;广州医学院,2012.
[37]DARNELL J C,FRASER C E,MOSTOVETSKY O,et al.Kissing complex RNAs mediate interaction between the Fragile-Xmental retardation protein KH2 domain and brain polyribosomes[J].Genes Dev,2005,19(8):903-18.
[38]SIOMI H,CHOI M,SIOMI M C,et al.Essential role for KHdomains in RNA binding:impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome[J].Cell,1994,77(1):33-9.
[39]AITKEN C E,LORSCH J R.A mechanistic overview of translation initiation in eukaryotes[J].Nat Struct Mol Biol,2012,19(6):568-76.
[40]NAPOLI I,MERCALDO V,BOYL P P,et al.The fragile Xsyndrome protein represses activity-dependent translation through CYFIP1,a new 4E-BP[J].Cell,2008,134(6):1042-54.
[41]EDBAUER D,NEILSON J R,FOSTER K A,et al.Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132[J].Neuron,2010,65(3):373-84.
[42]MUDDASHETTY R S,NALAVADI V C,GROSS C,et al.Reversible inhibition of PSD-95 mRNA translation by miR-125a,FMRP phosphorylation,and mGluR signaling[J].Mol Cell,2011,42(5):673-88.
[43]ROVOZZO R,KORZA G,BAKER M W,et al.CGG Repeats in the 5'UTR of FMR1 RNA Regulate Translation of Other RNAs Localized in the Same RNA Granules[J].PLoS One,2016,11(12):e0168204.
[44]WALTEREIT R,DAMMERMANN B,WULFF P,et al.Arg3.1/Arc mRNA induction by Ca2+and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation[J].J Neurosci,2001,21(15):5484-93.
[45]CHOWDHURY S,SHEPHERD J D,OKUNO H,et al.Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPAreceptor trafficking[J].Neuron,2006,52(3):445-59.
[46]ZHANG P,ABDELMOHSEN K,LIU Y,et al.Novel RNA-and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity[J].Nat Commun,2015,6(8888.
[47]COLLINS S C,COFFEE B,BENKE P J,et al.Array-based FMR1 sequencing and deletion analysis in patients with a fragile Xsyndrome-like phenotype[J].PLoS One,2010,5(3):e9476.
[2]ELTZER M M,BAKER M W,HONG J,et al.Prevalence of CGGexpansions of the FMR1 gene in a US population-based sample[J].Am J Med Genet B Neuropsychiatr Genet,2012,159B(5):589-97.
[3]HUNTER J,RIVERO-ARIAS O,ANGELOV A,et al.Epidemiology of fragile X syndrome:a systematic review and meta-analysis[J].Am J Med Genet A,2014,164A(7):1648-58.
[4]TASSONE F,IONG K P,TONG T H,et al.FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States[J].Genome Med,2012,4(12):100.
[5]PESSO R,BERKENSTADT M,CUCKLE H,et al.Screening for fragile X syndrome in women of reproductive age[J].Prenat Diagn,2000,20(8):611-4.
[6]SALDARRIAGA W,LEIN P,GONZALEZ TESHIMA L Y,et al.Phenobarbital use and neurological problems in FMR1 premutation carriers[J].Neurotoxicology,2016,53(141-7.
[7]WHEELER A C,BAILEY D B,JR.,BERRY-KRAVIS E,et al.Associated features in females with an FMR1 premutation[J].JNeurodev Disord,2014,6(1):30.
[8]HAMLIN A A,SUKHAREV D,CAMPOS L,et al.Hypertension in FMR1 premutation males with and without fragile X-associated tremor/ataxia syndrome(FXTAS)[J].Am J Med Genet A,2012,158A(6):1304-9.
[9]AU J,AKINS R S,BERKOWITZ-SUTHERLAND L,et al.Prevalence and risk of migraine headaches in adult fragile Xpremutation carriers[J].Clin Genet,2013,84(6):546-51.
[10]HAMLIN A,LIU Y,NGUYEN D V,et al.Sleep apnea in fragile X premutation carriers with and without FXTAS[J].Am J Med Genet B Neuropsychiatr Genet,2011,156B(8):923-8.
[11]SUMMERS S M,COGSWELL J,GOODRICH J E,et al.Prevalence of restless legs syndrome and sleep quality in carriers of the fragile X premutation[J].Clin Genet,2014,86(2):181-4.
[12]LEEHEY M A,LEGG W,TASSONE F,et al.Fibromyalgia in fragile X mental retardation 1 gene premutation carriers[J].Rheumatology(Oxford),2011,50(12):2233-6.
[13]COFFEY S M,COOK K,TARTAGLIA N,et al.Expanded clinical phenotype of women with the FMR1 premutation[J].Am JMed Genet A,2008,146A(8):1009-16.
[14]FRANKE P,BARBE B,LEBOYER M,et al.Fragile X syndrome.II.Cognitive and behavioral correlates of mutations of the FMR-1gene[J].Eur Psychiatry,1996,11(5):233-43.
[15]KEYSOR C S,MAZZOCCO M M.A developmental approach to understanding Fragile X syndrome in females[J].Microsc Res Tech,2002,57(3):179-86.
[16]HAGERMAN R J,BERRY-KRAVIS E,HAZLETT H C,et al.Fragile X syndrome[J].Nat Rev Dis Primers,2017,3(17065.
[17]SALDARRIAGA W,TASSONE F,GONZALEZ-TESHIMA LY,et al.Fragile X syndrome[J].Colomb Med(Cali),2014,45(4):190-8.
[18]JACQUEMONT S,FARZIN F,HALL D,et al.Aging in individuals with the FMR1 mutation[J].Am J Ment Retard,2004,109(2):154-64.
[19]HAGERMAN P J,GRECO C M,HAGERMAN R J.A cerebellar tremor/ataxia syndrome among fragile X premutation carriers[J].Cytogenet Genome Res,2003,100(1-4):206-12.
[20]BERRY-KRAVIS E,LEWIN F,WUU J,et al.Tremor and ataxia in fragile X premutation carriers:blinded videotape study[J].Ann Neurol,2003,53(5):616-23.
[21]JACQUEMONT S,HAGERMAN R J,LEEHEY M,et al.Fragile X premutation tremor/ataxia syndrome:molecular,clinical,and neuroimaging correlates[J].Am J Hum Genet,2003,72(4):869-78.
[22]HAGERMAN R,HAGERMAN P.Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome[J].Lancet Neurol,2013,12(8):786-98.
[23]RAJARATNAM A,SHERGILL J,SALCEDO-ARELLANO M,et al.Fragile X syndrome and fragile X-associated disorders[J].F1000Res,2017,6(2112.
[24]BROUWER J R,WILLEMSEN R,OOSTRA B A.The FMR1gene and fragile X-associated tremor/ataxia syndrome[J].Am JMed Genet B Neuropsychiatr Genet,2009,150B(6):782-98.
[25]ASHLEY A E,SHERMAN S L.Population dynamics of a meiotic/mitotic expansion model for the fragile X syndrome[J].Am J Hum Genet,1995,57(6):1414-25.
[26]WOHRLE D,KOTZOT D,HIRST M C,et al.A microdeletion of less than 250 kb,including the proximal part of the FMR-Igene and the fragile-X site,in a male with the clinical phenotype of fragile-X syndrome[J].Am J Hum Genet,1992,51(2):299-306.
[27]TARLETON J,KENNESON A,TAYLOR A K,et al.A single base alteration in the CGG repeat region of FMR1:possible effects on gene expression and phenotype[J].J Med Genet,2002,39(3):196-200.
[28]COLLINS S C,BRAY S M,SUHL J A,et al.Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males[J].Am J Med Genet A,2010,152A(10):2512-20.
[29]GRONSKOV K,BRONDUM-NIELSEN K,DEDIC A,et al.Anonsense mutation in FMR1 causing fragile X syndrome[J].Eur JHum Genet,2011,19(4):489-91.
[30]HAGERMAN R J,HAGERMAN P.Fragile X-associated tremor/ataxia syndrome-features,mechanisms and management[J].Nat Rev Neurol,2016,12(7):403-12.
[31]TASSONE F,HAGERMAN R J,TAYLOR A K,et al.Elevated levels of FMR1 mRNA in carrier males:a new mechanism of involvement in the fragile-X syndrome[J].Am J Hum Genet,2000,66(1):6-15.
[32]TASSONE F,HAGERMAN R J,CHAMBERLAIN W D,et al.Transcription of the FMR1 gene in individuals with fragile Xsyndrome[J].Am J Med Genet,2000,97(3):195-203.
[33]KENNESON A,ZHANG F,HAGEDORN C H,et al.Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers[J].Hum Mol Genet,2001,10(14):1449-54.
[34]TASSONE F,BEILINA A,CAROSI C,et al.Elevated FMR1mRNA in premutation carriers is due to increased transcription[J].RNA,2007,13(4):555-62.
[35]JIN P,ZARNESCU D C,CEMAN S,et al.Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway[J].Nat Neurosci,2004,7(2):113-7.
[36]段现来.脆性X相关疾病FMR1基因突变筛查和致病性分析[D];广州医科大学;广州医学院,2012.
[37]DARNELL J C,FRASER C E,MOSTOVETSKY O,et al.Kissing complex RNAs mediate interaction between the Fragile-Xmental retardation protein KH2 domain and brain polyribosomes[J].Genes Dev,2005,19(8):903-18.
[38]SIOMI H,CHOI M,SIOMI M C,et al.Essential role for KHdomains in RNA binding:impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome[J].Cell,1994,77(1):33-9.
[39]AITKEN C E,LORSCH J R.A mechanistic overview of translation initiation in eukaryotes[J].Nat Struct Mol Biol,2012,19(6):568-76.
[40]NAPOLI I,MERCALDO V,BOYL P P,et al.The fragile Xsyndrome protein represses activity-dependent translation through CYFIP1,a new 4E-BP[J].Cell,2008,134(6):1042-54.
[41]EDBAUER D,NEILSON J R,FOSTER K A,et al.Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132[J].Neuron,2010,65(3):373-84.
[42]MUDDASHETTY R S,NALAVADI V C,GROSS C,et al.Reversible inhibition of PSD-95 mRNA translation by miR-125a,FMRP phosphorylation,and mGluR signaling[J].Mol Cell,2011,42(5):673-88.
[43]ROVOZZO R,KORZA G,BAKER M W,et al.CGG Repeats in the 5'UTR of FMR1 RNA Regulate Translation of Other RNAs Localized in the Same RNA Granules[J].PLoS One,2016,11(12):e0168204.
[44]WALTEREIT R,DAMMERMANN B,WULFF P,et al.Arg3.1/Arc mRNA induction by Ca2+and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation[J].J Neurosci,2001,21(15):5484-93.
[45]CHOWDHURY S,SHEPHERD J D,OKUNO H,et al.Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPAreceptor trafficking[J].Neuron,2006,52(3):445-59.
[46]ZHANG P,ABDELMOHSEN K,LIU Y,et al.Novel RNA-and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity[J].Nat Commun,2015,6(8888.
[47]COLLINS S C,COFFEE B,BENKE P J,et al.Array-based FMR1 sequencing and deletion analysis in patients with a fragile Xsyndrome-like phenotype[J].PLoS One,2010,5(3):e9476.