脑性瘫痪(简称脑瘫)是儿童最常见的先天性运动障碍,然而,其内在的分子机制尚不明确。越来越多的证据表明,遗传因素在脑瘫的发病机制中起着举足轻重的作用。本团队对120个特发性脑瘫家庭进行了深入的遗传学分析,并在45%的患者中发现了潜在的有害遗传变异。通过对114个已知的脑瘫相关基因的整理,从遗传和功能两个方面确定了这些基因的特征,并根据这些基因的表达模式和相关的智力障碍提出二元分类系统。根据这一系统,对其中两个有代表性的基因TYW1和GPAM的致病机理进行深入探讨。综上所述,我们的发现为脑瘫病因学提供了新颖而有趣的分子机制,并为未来的治疗策略提供了新的方向。
Abstract
Cerebral palsy is the most prevalent physical disability in children. However, its inherent molecular mechanisms remain unclear.More and more evidences have showed that genetic factors play a pivotal role in the pathogenesis of cerebral palsy.Our research team has performed in-depth clinical and molecular analysis on 120 idiopathic cerebral palsy families, and identified underlying detrimental genetic variants in 45% of these patients.By a compilation of 114 known cerebral-palsy-related genes, characteristic features has been identified in terms of inheritance and function, from which a dichotomous classification system are proposed according to the expression patterns of these genes and associated cognitive impairments.Using this algorithm, the pathogenic mechanisms of two representative gene mutations, TYW1 and GPAM, are explored in depth.Taken together, our findings provide a novel and interesting mechanism for the etiology of cerebral palsy and insights for future therapeutic strategies.
关键词
脑瘫 /
遗传因素 /
致病突变 /
二元分类系统
Key words
cerebral palsy /
genetic factor /
disease-causing mutation /
dichotomous classification system
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参考文献
[1] Colver A, Fairhurst C, Pharoah PO: Cerebral palsy[J]. Lancet,2014, 383:1240-1249.
[2] Moreno-De-Luca A, Ledbetter DH, Martin CL: Genetic [corrected] insights into the causes and classification of [corrected] cerebral palsies[J]. Lancet Neurol,2012, 11:283-292.
[3] Novak I, Morgan C, Adde L, et al. Early, accurate diagnosis and early intervention in cerebral palsy: Advances in diagnosis and treatment[J]. JAMA Pediatr,2017, 171:897-907.
[4] Korzeniewski SJ, Slaughter J, Lenski M, et al. The complex aetiology of cerebral palsy[J]. Nat Rev Neurol,2018, 14:528-543.
[5] Graham HK, Rosenbaum P, Paneth N, et al. Cerebral palsy[J]. Nat Rev Dis Primers, 2016, 2:15082.
[6] MacLennan AH, Thompson SC, Gecz J. Cerebral palsy: causes, pathways, and the role of genetic variants[J]. Am J Obstet Gynecol,2015, 213:779-788.
[7] Hemminki K, Li X, Sundquist K, et al. High familial risks for cerebral palsy implicate partial heritable aetiology[J]. Paediatr Perinat Epidemiol, 2007, 21:235-241.
[8] Garne E, Dolk H, Krägeloh-Mann I, et al. Cerebral palsy and congenital malformations[J]. Eur J Paediatr Neurol, 2008, 12:82-88.
[9] O'Callaghan ME, MacLennan AH, Haan EA, et al. The genomic basis of cerebral palsy: A HuGE systematic literature review[J]. Hum Genet, 2009, 126:149-172.
[10] Fahey MC, Maclennan AH, Kretzschmar D, et al. The genetic basis of cerebral palsy[J]. Dev Med Child Neurol, 2017, 59:462-469.
[11] Turner TN, Coe BP, Dickel DE, et al. Genomic patterns of de novo mutation in simplex autism[J]. Cell, 2017, 171:710-722.e712.
[12] Hu H, Kahrizi K, Musante L, et al. Genetics of intellectual disability in consanguineous families[J]. Mol Psychiatry, 2019, 24:1027-1039.
[13] Satterstrom FK, Kosmicki JA, Wang J, et al.: Large-Scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism[J]. Cell, 2020, 180:568-584.e523.
[14] Li N, Zhou P, Tang H, et al. In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy[J]. Brain, 2021.doi:10.1016/j.cell.2019.12.036(2020).
[15] Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders[J]. Nat Rev Genet, 2016, 17:9-18.
[16] Rak R, Dahan O, Pilpel Y. Repertoires of tRNAs: The couplers of genomics and proteomics[J]. Annu Rev Cell Dev Biol, 2018, 34:239-264.
[17] Schaffer AE, Pinkard O, Coller JM: tRNA Metabolism and Neurodevelopmental Disorders[J]. Annu Rev Genomics Hum Genet, 2019, 20:359-387.
[18] El Yacoubi B, Bailly M, de Crécy-Lagard V: Biosynthesis and function of posttranscriptional modifications of transfer RNAs[J]. Annu Rev Genet, 2012, 46:69-95.
[19] Molina-Gonzalez I, Miron VE: Astrocytes in myelination and remyelination[J]. Neurosci Lett, 2019, 713:134532.
[20] Kıray H, Lindsay SL, Hosseinzadeh S, et al. The multifaceted role of astrocytes in regulating myelination[J]. Exp Neurol, 2016, 283:541-549.
[21] Brookes KJ, Chen W, Xu X, et al. Association of fatty acid desaturase genes with attention-deficit/hyperactivity disorder[J]. Biol Psychiatry, 2006, 60:1053-1061.
[22] Pinto D, Delaby E, Merico D, et al.: Convergence of genes and cellular pathways dysregulated in autism spectrum disorders[J]. Am J Hum Genet, 2014, 94:677-694.
[23] Jungerius BJ, Hoogendoorn ML, Bakker SC, et al. An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia[J]. Mol Psychiatry, 2008, 13:1060-1068.
[24] Schmitt A, Gofferje V, Weber M, et al. The brain-specific protein MLC1 implicated in megalencephalic leukoencephalopathy with subcortical cysts is expressed in glial cells in the murine brain[J]. Glia, 2003, 44:283-295.
[25] Dietrich J, Lacagnina M, Gass D, Richfield E, Mayer-Pröschel M, Noble M, Torres C, Pröschel C: EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy[J]. Nat Med, 2005, 11:277-283.
基金
国家自然科学基金面上项目(81671067,81974163);广州市科创委重大项目(201510192218459)
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