Журнал высшей нервной деятельности им. И.П. Павлова, 2022, T. 72, № 3, стр. 293-316

Спектр синдромальных нарушений при экспансии CGG-повторов промотора гена FMR1: патогенетические механизмы и клинические проявления

Д. С. Переверзева 1, С. А. Тюшкевич 1, Е. В. Улас 2, Н. Л. Горбачевская 13*

1 Московский государственный психолого-педагогический университет (ФГБОУ ВО МГППУ)
Москва, Россия

2 Институт белка РАН
Пущино, Россия

3 Научный центр психического здоровья (ФГБНУ НЦПЗ)
Москва, Россия

* E-mail: gorbachevskaya@yandex.ru

Поступила в редакцию 21.11.2020
После доработки 01.03.2021
Принята к публикации 02.03.2021

Аннотация

Спектр заболеваний, ассоциированных с ломкой хромосомой Х (FXSD) объединяет следующие клинические синдромы: синдром умственной отсталости, сцепленной с ломкой хромосомой Х (fragile X syndrome, FXS), синдром тремора и атаксии (FXTAS), синдром первичной овариальной недостаточности (FXPOI), группа нейропсихиатрических нарушений (FXAND). Причиной их возникновения являются динамические мутации гена FMR1, вызванные экспансией тринуклеотидных повторов в промоторе гена. Синдром FXS (умственная отсталость, РАС, СДВГ) возникает при полной мутации гена FMR1 (увеличение количества CGG-повторов свыше 200), сопровождающейся полным или частичным подавлением экспрессии белка FMRP. Клинические проявления FXTAS, FXPOI, FXAND могут возникнуть у лиц-носителей премутации FMR1 (диапазон значений количества CGG-повторов от 55 до 200). К основным патогенетическим механизмам этих заболеваний относят снижение экспрессии FMRP и накопление мРНК FMR1, содержащей увеличенное количество повторов. Настоящий обзор посвящен анализу гено-фенотипических отношений внутри спектра состояний, ассоциированных с динамическими мутациями FMR1. В статье представлен анализ взаимосвязи молекулярных механизмов (дефицит FMRP, трансляция атипичных изоформ, усиление функции мРНК FMR1) и клинических проявлений (уровень когнитивного развития, тяжесть РАС, тяжесть симптомов FXTAS, FXPOI и FXAND).

Ключевые слова: динамические мутации, FMRP, экспансия CGG-повторов FMR1, мРНК-транскрипция, умственная отсталость, расстройства аутистического спектра, СДВГ, FXSD, FXTAS, FXPOI, FXAND

Список литературы

  1. Переверзева Д.С., Данилина К.К., Горбачевская Н.Л. Общие и специфические механизмы нарушения развития зрительной когнитивной функции у лиц с дефицитом белка FMRP. Журн. высш. нервн. деят. им. И.П. Павлова. 2015. 65(3): 259–270.

  2. Переверзева Д.С., Тюшкевич С.А., Горбачевская Н.Л., Мамохина У.А., Данилина К.К. Гетерогенность клинической картины при синдромах, ассоциированных с динамическими мутациями гена FMR1. Журнал неврологии и психиатрии им. С.С. Корсакова. 2019. 119(7): 103–111.

  3. Тюшкевич С.А., Воинова В.Ю., Юров И.Ю., Горбачевская Н.Л. Характер когнитивных нарушений у детей с синдромом умственной отсталости, сцепленной с ломкой хромосомой Х. Дефектология. 2010. 3: 29–37.

  4. Юдкин Д.В., Лемская Н.А., Грищенко И.В., Дольский А.А. Изменение состава хроматина при экспансии тринуклеотидного повтора CGG в гене FMR1. Молекулярная биология. 2015. 49(2): 205–211.

  5. Abitbol M., Menini C., Delezoide A.-L., Rhyner T., Vekemans M., Mallet J. Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain. Nature. Genet. 1993. 4: 147–153.

  6. Allen E.G., Sullivan A.K., Marcus M., Small C., Dominguez C., Epstein M.P., Charen K., He W., Taylor K.C., Sherman S.L. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum. Reprod. 2007. 22(8): 2142–2152.

  7. Antar L.N., Li C., Zhang H., Carroll R.C., Bassell G.J. Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol. Cell. Neurosci. 2006. 32: 37–48.

  8. Arocena D.G., Iwahashi C.K., Won N., Beilina A., Ludwig A.L., Tassone F., Schwartz P.H., Hagerman P.J. Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells. Hum. Mol. Genet. 2005. 14: 3661–3671.

  9. Arpone M., Baker E.K., Bretherton L., Bui M., Li X., Whitaker S., Dissanayake C., Cohen J., Hickerton C., Rogers C., Field M., Elliott J., Aliaga S.M., Ling L., Francis D., Hearps S., Hunter M.F., Amor D.J., Godler D.E. Intragenic DNA methylation in buccal epithelial cells and intellectual functioning in a paediatric cohort of males with fragile X. Sci. Rep. 2018. 8(1): 3644.

  10. Ascano M.Jr., Mukherjee N., Bandaru P., Miller J.B., Nusbaum J.D., Corcoran D.L., Langlois C., Munschauer M., Dewell S., Hafner M., Williams Z., Ohler U., Tuschl T. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature. 2012. 492: 382–386.

  11. Ashwood P., Nguyen D.V., Hessl D., Hagerman R.J., Tassone F. Plasma cytokine profiles in Fragile X subjects: is there a role for cytokines in the pathogenesis? Brain. Behav. Immun. 2010. 24(6): 898–902.

  12. Bailey D.B.Jr., Raspa M., Olmsted M., Holiday D.B. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am. J. Med. Genet. 2008. 146A(16): 2060–2069.

  13. Baker E.K., Arpone M., Aliaga S.M., Bretherton L., Kraan C.M., Bui M., Slater H.R., Ling L., Francis D., Hunter M.F., Elliott J., Rogers C., Field M., Cohen J., Cornish K., Santa Maria L., Faundes V., Curotto B., Morales P., Trigo C., Salas I., Alliende A.M., Amor D.J., Godler D.E. Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features. Mol. Autism. 2019. 3: 10–21.

  14. Baker E.K., Arpone M., Kraan C., Bui M., Rogers C., Field M., Bretherton L., Ling L., Ure A., Cohen J., Hunter M.F., Santa María L., Faundes V., Curotto B., Morales P., Trigo C., Salas I., Alliende A., Amor D.J., Godler D.E. FMR1 mRNA from full mutation alleles is associated with ABC-CFX scores in males with fragile X syndrome. Sci. Rep. 2020. 10(1): 11701.

  15. Baron-Cohen S., Ring H.A., Bullmore E.T., Wheelwright S., Ashwin C., Williams S.C. The amygdala theory of autism. Neurosci. Biobehav. Rev. 2000. 24(3): 355–364.

  16. Basuta K., Schneider A., Gane L., Polussa J., Woodruff B., Pretto D., Hagerman R., Tassone F. High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome. Am. J. Med. Genet. 2015. 167A (9): 2154–2161.

  17. Bechara E.G., Didiot M.C., Melko M., Davidovic L., Bensaid M., Martin P., Castets M., Pognonec P., Khandjian E.W., Moine H., Bardoni B. A novel function for fragile X mental retardation protein in translational activation. PLoS. Biol. 2009. 7: E16–E16.

  18. Berman R.F., Buijsen R.A., Usdin K., Pintado E., Kooy F., Pretto D., Pessah I.N., Nelson D.L., Zalewski Z., Charlet-Bergeurand N., Willemsen R., Hukema R.K. Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome. J. Neurodev. Disord. 2014. 6(1): 25.

  19. Berry-Kravis E., Potanos K., Weinberg D., Zhou L., Goetz C.G. Fragile X-associated tremor/ataxia syndrome in sisters related to X-inactivation. Ann. Neurol. 2005. 57: 144–147.

  20. Brown M.R., Kronengold J., Gazula V.R., Chen Y., Strumbos J.G., Sigworth F.J., Navaratnam D., Kaczmarek L.K. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat. Neurosci. 2010. 13: 819–821.

  21. Budimirovic D.B., Kaufmann W.E. What can we learn about autism from studying fragile X syndrome? Dev. Neurosci. 2011. 33(5): 379–394.

  22. Budimirovic D.B, Subramanian M. Neurobiology of Autism and Intellectual Disability: fragile X Syndrome. 2 ed. In: Johnston M., Adams H., Fatemi A., editors. London: Oxford University Press; 2016.

  23. Buijsen R.A., Visser J.A., Kramer P., Severijnen E.A., Gearing M., Charlet-Berguerand N., Sherman S.L., Berman R.F., Willemsen R., Hukema R.K. Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency. Hum. Reprod. 2016. 31(1): 158–168.

  24. Clifford S., Dissanayake C., Bui Q.M., Huggins R., Taylor A.K., Loesch D.Z. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. Journal of Autism and Developmental Disorders. 2007. 37(4): 738–747.

  25. Cohen S., Masyn K., Adams J., Hessl D., Rivera S., Tassone F., Brunberg J., DeCarli C., Zhang L., Cogswell J., Loesch D., Leehey M., Grigsby J., Hagerman P.J., Hagerman R. Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome. Neurology. 2006. 67(8): 1426–1431.

  26. Colak D., Zaninovic N., Cohen M.S., Rosenwaks Z., Yang W.Y., Gerhardt J., Disney M.D., Jaffrey S.R. Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science. 2014. 343(6174): 1002–1005.

  27. Cornish K.M., Kogan C.S., Li L., Turk J., Jacquemont S., Hagerman R.J. Lifespan changes in working memory in fragile X premutation males. Brain. Cogn. 2009. 69(3): 551–558.

  28. Cornish K.M., Kraan C.M., Bui Q.M., Bellgrove M.A., Metcalfe S.A., Trollor J.N., Hocking D.R., Slater H.R., Inaba Y., Li X., Archibald A.D., Turbitt E., Cohen J., Godler D.E. Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women. Neurology. 2015. 84(16): 1631–1638.

  29. de Vries B.B., Wiegers A.M., Smits A.P., Mohkamsing S., Duivenvoorden H.J., Fryns J.P., Curfs L.M., Halley D.J., Oostra B.A., van den Ouweland A.M., Nier- meijer M.F. Mental status of females with an FMR1 gene full mutation. Am. J. Hum. Genet. 1996. 58(5): 1025–1032.

  30. Dean D.D., Agarwal S., Muthuswamy S. Defining the role of FMR1 gene in unexplained recurrent spontaneous abortion. J Assist Reprod Genet. 2019. 36(11): 2245–2250.

  31. DeMarco B., Stefanovic S., Williams A., Moss K.R., Anderson B.R., Bassell G.J., Mihailescu M.R. FMRP – G-quadruplex mRNA - miR-125a interactions: Implications for miR-125a mediated translation regulation of PSD-95 mRNA. PLoS One. 2019. 14(5): e0217275.

  32. Didiot M.C., Tian Z., Schaeffer C., Subramanian M., Mandel J.L., Moine H. The G-quartet containing FMRP binding site in FMR1 mRNA is a potent exonic splicing enhancer. Nucleic. Acids. Res. 2008. 36: 4902–4912.

  33. Doll C.A., Yergert K.M., Appel B.H. The RNA binding protein fragile X mental retardation protein promotes myelin sheath growth Glia. 2020. 68(3): 495–508.

  34. Drouin R., Angers M., Dallaire N., Rose T.M., Khandjian W., Rousseau F. Structural and functional characterization of the human FMR1 promoter reveals similarities with the hnRNP-A2 promoter region. Hum. Mol. Genet. 1997. 6: 2051–2060.

  35. Ennis S., Ward D., Murray A. Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers. Eur. J. Hum. Genet. 2006. 14(2): 253–255.

  36. Farzin F., Perry H., Hessl D., Loesch D., Cohen J., Bacalman S., Gane L., Tassone F., Hagerman P., Hagerman R. Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation. J Dev Behav Pediatr. 2006. 27(2 Suppl): 137–144. PMID: 16685180.https://doi.org/10.1097/00004703-200604002-00012

  37. Field M., Dudding-Byth T., Arpone M., Baker E.K., Aliaga S.M., Rogers C., Hickerton C., Francis D., Phelan D.G., Palmer E.E., Amor D.J., Slater H., Bretherton L., Ling L., Godler D.E. Significantly Elevated FMR1 mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing. Int J Mol Sci. 2019. 20(16): 3907.

  38. Friedman-Gohas M., Elizur S.E., Dratviman-Storobinsky O., Aizer A., Haas J., Raanani H., Orvieto R., Cohen Y. FMRpolyG accumulates in FMR1 premutation granulosa cells. J Ovarian Res. 2020. 13(1): 22.

  39. Gallego P.K., Burris J.L., Rivera S.M. Visual motion processing deficits in infants with the fragile X premutation. J. Neurodev Disord. 2014. 6(1): 29. https://doi.org/10.1186/1866-1955-6-29

  40. Garcia-Alegria E., Ibáñez B., Mínguez M., Poch M., Valiente A., Sanz-Parra A., Martinez-Bouzas C., Beristain E., Tejada M.I. Analysis of FMR1 gene expression in female premutation carriers using robust segmented linear regression models. RNA. 2007. 13(5): 756–762.

  41. Godler D.E., Slater H.R., Bui Q.M., Ono M., Gehling F., Francis D., Amor D.J., Hopper J.L., Hagerman R., Loesch D.Z. FMR1 intron 1 methylation predicts FMRP expression in blood of female carriers of expanded FMR1 alleles. J. Mol. Diagn. 2011. 13(5): 528–536.

  42. Godler D.E., Slater H.R., Bui Q.M., Storey E., Ono M.Y., Gehling F., Inaba Y., Francis D., Hopper J.L., Kinsella G., Amor D.J., Hagerman R.J., Loesch D.Z. Fragile X mental retardation 1 (FMR1) intron 1 methylation in blood predicts verbal cognitive impairment in female carriers of expanded FMR1 alleles: evidence from a pilot study. Clin. Chem. 2012. 58(3): 590–598.

  43. Godler D.E., Tassone F., Loesch D.Z., Taylor A.K., Gehling F., Hagerman R.J., Burgess T., Ganesamoorthy D., Hennerich D., Gordon L., Evans A., Choo K.H., Slater H.R. Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio. Hum. Mol. Genet. 2010. 19(8): 1618–1632.

  44. Godler D.E. Treatment and diagnosis of epigenetic disorders and conditions. Google Patents; 2012.

  45. Greco C.M., Berman R.F., Martin R.M., Tassone F., Schwartz P.H., Chang A., Trapp B.D., Iwahashi C., Brunberg J., Grigsby J., Hessl D., Becker E.J., Papazian J., Leehey M.A., Hagerman R.J., Hagerman P.J. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain. 2006. 129 (Pt 1): 243–255.

  46. Hagerman P.J., Hagerman R.J. The fragile-X premutation: a maturing perspective. Am. J. Hum. Genet. 2004. 74(5): 805–816.

  47. Hagerman R.J., Berry-Kravis E., Hazlett H.C., Bailey D.B. Jr., Moine H., Kooy R.F., Tassone F., Gantois I., Sonenberg N., Mandel J.L., Hagerman P.J. Fragile X syndrome. Nat. Rev. Dis. Primers. 2017. 3: 17065.

  48. Hagerman R.J., Hull C.E., Safanda J.F., Carpenter I., Staley L.W., O’Connor R.A., Seydel C., Mazzocco M.M., Snow K., Thibodeau S.N., Kuhl D., Nelson D.L., Caskey C.Th., Taylor A.K. High functioning fragile X males: demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. Am J Med Genet. 1994. 51(4): 298–308.

  49. Hagerman R.J., Protic D., Rajaratnam A., Salcedo-Arellano M.J., Aydin E.Y., Schneider A. Fragile X-Associated Neuropsychiatric Disorders (FXAND). Frontiers in psychiatry. 2018. 9: 564.

  50. Hall D., Pickler L., Riley K., Tassone F., Hagerman R. Parkinsonism and cognitive decline in a fragile X mosaic male. Mov. Disord. 2010. 25(10): 1523–1524.

  51. Hall D.A., Robertson-Dick E.E., O’Keefe J.A., Hadd A.G., Zhou L., Berry-Kravis E. X-inactivation in the clinical phenotype of fragile X premutation carrier sisters. Neurology. Genetics. 2016. 2(1): e45.

  52. Hall D.A., Nag S., Ouyang B., Bennett D.A., Liu Y., Ali A., Zhou L., Berry-Kravis E. Fragile X Gray Zone Alleles Are Associated With Signs of Parkinsonism and Earlier Death. Mov. Disord. 2020. 35(8): 1448–1456.

  53. Hashimoto R.I., Backer K.C., Tassone F., Randi J., Hagerman R.J., Rivera S.M. An fMRI study of the prefrontal activity during the performance of a work- ing memory task in premutation carriers of the fragile X mental retardation 1 gene with and without fragile X-associated tremor/ataxia syndrome (FX-TAS). Journal of Psychiatric Research. 2010. 45(1): 36–43.

  54. Hatton D.D., Sideris J., Skinner M., Mankowski J., Bailey D.B. Jr, Roberts J., Mirrett P. Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP. Am. J. Med. Genet. A. 2006. 140A(17): 1804–1813.

  55. Heine-Suñer D., Torres-Juan L., Morlà M., Busquets X., Barceló F., Picó G., Bonilla L., Govea N., Bernués M., Rosell J. Fragile-X syndrome and skewed X-chromosome inactivation within a family: a female member with complete inactivation of the functional X chromosome. Am J Med Genet A. 2003. 122A(2): 108–114.

  56. Hessl D., Dyer-Friedman J., Glaser B., Wisbeck J., Barajas R.G., Taylor A., Reiss A.L. The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome. Pediatrics. 2001. 108(5): E88.

  57. Hessl D., Tassone F., Loesch D.Z., Berry-Kravis E., Leehey M.A., Gane L.W., Barbato I., Rice C., Gould E., Hall D.A., Grigsby J., Wegelin J.A., Harris S., Lewin F., Weinberg D., Hagerman P.J., Hagerman R.J. Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005. 139B(1): 115–121.

  58. Hessl D., Nguyen D.V., Green C., Chavez A., Tassone F., Hagerman R. J., Senturk D., Schneider A., Lightbody A., Reiss A.L., Hall S. A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome. Journal of neurodevelopmental disorders. 2009. 1(1): 33–45.

  59. Hinds H.L., Ashley C.T., Sutcliffe J.S., Nelson D.L., Warren S.T., Housman D.E., Schalling M. Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nat. Genet. 1993. 3(1): 36–43.

  60. Hukema R.K., Buijsen R.A., Schonewille M., Raske C., Severijnen L.A., Nieuwenhuizen-Bakker I., Verhagen R.F., van Dessel L., Maas A., Charlet-Berguerand N., De Zeeuw C.I., Hagerman P.J., Berman R.F., Willemsen R. Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. Hum. Mol. Genet. 2015. 24(17): 4948–4957.

  61. Jacquemont S., Hagerman R.J., Leehey M.A., Hall D.A., Levine R.A., Brunberg J.A., Zhang L., Jardini T., Gane L.W., Harris S.W., Herman K., Grigsby J., Greco C.M., Berry-Kravis E., Tassone F., Hagerman P.J. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004. 291(4): 460–469.

  62. Jacquemont S., Leehey M.A., Hagerman R.J., Beckett L.A., Hagerman P.J. Size bias of fragile X premutation alleles in late-onset movement disorders. J. Med. Genet. 2006. 43(10): 804–809.

  63. Jalnapurkar I., Rafika N., Tassone F., Hagerman R. Immune mediated disorders in women with a fragile X expansion and FXTAS. Am. J. Med. Genet. A. 2015. 167A(1): 190–7.

  64. Jiraanont P., Kumar M., Tang H.T., Espinal G., Hagerman P.J., Hagerman R.J., Chutabhakdikul N., Tassone F. Size and methylation mosaicism in males with Fragile X syndrome. Expert. Rev. Mol. Diagn. 2017a. 17(11): 1023–1032.

  65. Jiraanont P., Sweha S.R., AlOlaby R.R., Silva M., Tang H.T., Durbin-Johnson B., Schneider A., Espinal G.M., Hagerman P.J., Rivera S.M., Hessl D., Hagerman R.J., Chutabhakdikul N., Tassone F. Clinical and molecular correlates in fragile X premutation females. eNeurologicalSci. 2017b. 7: 49–56.

  66. Kenna H.A., Tartter M., Hall S.S. High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013. 162(8): 872–878.

  67. Kenny P.J., Zhou H., Kim M., Skariah G., Khetani R.S., Drnevich J., Arcila M.L., Kosik K.S., Ceman S. MOV10 and FMRP regulate AGO2 association with microRNA recognition elements. Cell Rep. 2014. 9: 1729–1741.

  68. Kim K., Hessl D., Randol J.L., Espinal G.M., Schneider A., Protic D., Aydin E.Y., Hagerman R.J., Hagerman P.J. Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions. PLoS One. 2019. 14(12): e0226811.

  69. Kim M., Bellini M., Ceman S. Fragile X mental retardation protein FMRP binds mRNAs in the nucleus. Mol. Cell. Biol. 2009. 29: 214–228.

  70. Kirchgessner C.U., Warren S.T., Willard H.F. X inactivation of the FMR1 fragile X mental retardation gene. Journal of medical genetics. 1995. 32(12): 925–929.

  71. Kover S.T., Pierpont E.I., Kim J.S., Brown W.T., Abbeduto L. A neurodevelopmental perspective on the acquisition of nonverbal cognitive skills in adolescents with fragile X syndrome. Dev. Neuropsychol. 2013. 38(7): 445–460.

  72. Kraan C.M., Godler D.E., Amor D.J. Epigenetics of fragile X syndrome and fragile X-related disorders. Dev. Med. Child. Neurol. 2019. 61(2): 121–127.

  73. Krans A., Kearse M.G., Todd P.K. Repeat-associated nonAUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome. Ann Neurol. 2016. 80: 871–881.

  74. Kumari D., Usdin K. Interaction of the transcription factors USF1, USF2, and α-Pal/Nrf-1 with the FMR1 promoter. Implications for fragile X mental retardation syndrome. J. Biol. Chem. 2001. 276: 4357–4364.

  75. Lachiewicz A., Dawson D., Spiridigliozzi G. Indicators of anxiety and depression in women with the fragile X premutation: assessment of a clinical sample. J. Intellect. Disabil. Res. 2010. 54(7): 597–610.

  76. Leehey M.A., Berry-Kravis E., Goetz C.G., Zhang L., Hall D.A., Li L., Rice C.D., Lara R., Cogswell J., Reynolds A., Gane L., Jacquemont S., Tassone F., Grigsby J., Hagerman R.J., Hagerman P.J. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008. 70(16 Pt 2): 1397–402.

  77. Loesch D.Z., Bui M.Q., Hammersley E. Psychological status in female carriers of premutation FMR1 allele showing a complex relationship with the size of CGG expansion. Clin. Genet. 2015. 87(2): 173–178.

  78. Loesch D.Z., Bui Q.M., Dissanayake C., Clifford S., Gould E., Bulhak-Paterson D., Tassone F., Tay-lor A.K., Hessl D., Hagerman R., Huggins R.M. Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci. Biobehav. Rev. 2007. 31(3): 315–326.

  79. Loesch D.Z., Godler D.E., Evans A., Bui Q.M., Gehling F., Kotschet K.E., Trost N., Storey E., Stimpson P., Kinsella G., Francis D., Thorburn D.R., Venn A., Slater H.R., Horne M. Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism. Genet. Med. 2011. 13: 392–399.

  80. Loesch D.Z., Huggins R.M., Hagerman R.J. Phenotypic variation and FMRP levels in fragile X. Ment. Retard. Dev. Disabil. Res. Rev. 2004. 10(1): 31–41.

  81. Loesch D.Z., Sherwell S., Kinsella G., Tassone F., Taylor A., Amor D., Sung S., Evans A. Fragile X-associated tremor/ataxia phenotype in a male carrier of unmethylated full mutation in the FMR1 gene. Clin. Genet. 2012. 82(1): 88–92.

  82. Loesch D.Z., Tassone F., Mellick G.D., Horne M., Rubio J.P., Bui M.Q., Francis D., Storey E. Evidence for the role of FMR1 gray zone alleles as a risk factor for parkinsonism in females. Mov Disord. 2018. 33(7): 1178–1181.

  83. Loesch D.Z., Churchyard A., Brotchie P., Marot M., Tassone F. Evidence for, and a spectrum of, neurological involvement in carriers of the fragile X premutation: FXTAS and beyond. Clin Genet. 2005. 67: 412–417.

  84. Loesch D., Hagerman R. Unstable mutations in the FMR1 gene and the phenotypes. Adv Exp Med Biol. 2012. 769: 78–114. https://doi.org/10.1007/978-1-4614-5434-2_6

  85. Lozano R., Rosero C., Hagerman R. Fragile X spectrum disorders. Intractable & Rare Diseases Research. 2014. 3(4): 134–146.

  86. Ludwig A.L., Espinal G.M., Pretto D., Jamal A.L., Arque G., Tassone F., Berman R.F., Hagerman P.J. CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size. Hum. Mol. Genet. 2014. 23: 3228–3238.

  87. Mailick M.R., Hong J., Greenberg J., Smith L., Sherman S. Curvilinear association of CGG repeats and age at menopause in women with FMR1 premutation expansions. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014. 165B(8): 705–711.

  88. Mankodi A., Thornton C.A. Myotonic syndromes. Curr. Opin.Neurol. 2002. 15: 545–552.

  89. McDuffie A., Abbeduto L., Lewis P., Kover S., Kim J.S., Weber A., Brown W.T. Autism spectrum disorder in children and adolescents with fragile X syndrome: within-syndrome differences and age-related changes. Am. J. Intellect. Dev. Disabil. 2010. 115(4): 307–326.

  90. Moore C.J., Daly E.M., Schmitz N., Tassone F., Tysoe C., Hagerman R.J., Hagerman P.J., Morris R.G., Murphy K.C., Murphy D.G. A neuropsychological investigation of male premutation carriers of fragile X syndrome. Neuropsychologia. 2004. 42: 1934–1947.

  91. Myrick L.K., Deng P.Y., Hashimoto H., Oh Y.M., Cho Y., Poidevin M.J., Suhl J.A., Visootsak J., Cavalli V., Jin P., Cheng X., Warren S.T., Klyachko V.A. Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures. Proc. Natl. Acad. Sci. U.S.A. 2015. 112: 949–956.

  92. Naumann A., Hochstein N., Weber S., Fanning E., Doerfler W. A distinct DNA-methylation boundary in the 5′-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome. Am. J. Hum. Genet. 2009. 85: 606–616.

  93. Nelson L.M., Covington S.N., Rebar R.W. An update: spontaneous premature ovarian failure is not an early menopause. Fertil. Steril. 2005. 283: 1327–1332.

  94. Nolin S.L., Glicksman A., Houck G.E. Jr, Brown W.T., Dobkin C.S. Mosaicism in fragile X affected males. Am. J. Med. Genet. 1994. 51(4): 509–512.

  95. Pastori C., Peschansky V.J., Barbouth D., Mehta A., Silva J.P., Wahlestedt C. Comprehensive analysis of the transcriptional landscape of the human FMR1 gene reveals two new long noncoding RNAs differentially expressed in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome. Hum. Genet 2014. 133: 59–67.

  96. Peprah E., He W., Allen E., Oliver T., Boyne A., Sherman S.L. Examination of FMR1 transcript and protein levels among 74 premutation carriers. J. Hum. Genet. 2010. 55(1): 66–68.

  97. Peschansky V.J., Pastori C., Zeier Z., Wentzel K., Velmeshev D., Magistri M., Silva J.P., Wahlestedt C. The long noncoding RNA FMR4 promotes proliferation of human neural precursor cells and epigenetic regulation of gene expression in trans. Mol. Cell. Neurosci. 2016. 74: 49–57.

  98. Pietrobono R., Pomponi M.G., Tabolacci E., Oostra B., Chiurazzi P., Neri G. Quantitative analysis of DNA demethylation and transcriptional reactivation of the FMR1 gene in fragile X cells treated with 5‑azadeoxycytidine. Nucleic. Acids. Res. 2002. 30: 3278–3285.

  99. Pretto D., Yrigollen C.M., Tang H.T., Williamson J., Espinal G., Iwahashi C.K., Durbin-Johnson B., Hagerman R.J., Hagerman P.J., Tassone F. Clinical and molecular implications of mosaicism in FMR1 full mutations. Front Genet. 2014a. 5: 318.

  100. Pretto D.I., Hunsaker M.R., Cunningham C.L., Greco C.M., Hagerman R.J., Noctor S.C., Hall D.A., Hagerman P.J., Tassone F. Intranuclear inclusions in a fragile X mosaic male. Transl. Neurodegener. 2013. 2(1): 10.

  101. Pretto D.I., Mendoza-Morales G., Lo J., Cao R., Hadd A., Latham G.J., Durbin-Johnson B., Hagerman R., Tassone F. CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles. J. Med. Genet. 2014b. 51(5): 309–318.

  102. Rajaratnam A., Shergill J., Salcedo-Arellano M., Saldarriaga W., Duan X., Hagerman R. Fragile X syndrome and fragile X-associated disorders. F1000Res. 2017. 6: 2112.

  103. Raspa M., Wylie A., Wheeler A.C., Kolacz J., Edwards A., Heilman K., Porges S.W. Sensory Difficulties in Children With an FMR1 Premutation. Front Genet. 2018 Aug 28; 9: 351. PMID: 30233641; PMCID: PMC6127619.https://doi.org/10.3389/fgene.2018.00351

  104. Roberts J.E., Bailey D.B., Mankowski J. Mood and anxiety disorders in females with the FMR1 premutation. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009a. 150(1): 130–139.

  105. Roberts J.E., Ezell J.E., Fairchild A.J., Klusek J., Thurman A.J., McDuffie A., Abbeduto L. Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2018. 177(7): 665–675.

  106. Rodriguez-Revenga L., Madrigal I., Badenas C., Xunclà M., Jiménez L., Milà M. Premature ovarian failure and fragile X female premutation carriers: no evidence for a skewed X-chromosome inactivation pattern. Menopause. 2009. 16(5): 944–949.

  107. Rodriguez-Revenga L., Madrigal I., Pagonabarraga J., Xunclà M., Badenas C., Kulisevsky J., Gomez B., Milà M. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur. J. Hum. Genet. 2009. 17(10): 1359–1362.

  108. Rousseau F., Heitz D., Biancalana V., Blumenfeld S., Kretz C., Boué J., Tommerup N., Van Der Hagen C., DeLozier-Blanchet C., Croquette M.F. Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N. Engl. J. Med. 1991. 325(24): 1673–1681.

  109. Salcedo-Arellano M.J., Dufour B., McLennan Y., Martinez-Cerdeno V., Hagerman R. Fragile X syndrome and associated disorders: Clinical aspects and pathology. Neurobiol Dis. 2020 Mar; 136: 104740.

  110. Santa María L., Pugin A., Alliende M.A., Aliaga S., Curotto B., Aravena T., Tang H.T., Mendoza-Morales G., Hagerman R., Tassone F. FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile. Clin. Genet. 2014. 86(4): 378–382.

  111. Schneider A., Johnston C., Tassone F. Broad autism spectrum and obsessive–compulsive symptoms in adults with the fragile X premutation. Clin. Neuropsychol. 2016. 30(6): 929–943.

  112. Sellier C., Buijsen RAM, He F., Natla S., Jung L., Tropel P., Gaucherot A., Jacobs H., Meziane H., Vincent A., Champy M.F., Sorg T., Pavlovic G., Wattenhofer-Donze M., Birling M.C., Oulad-Abdelghani M., Eberling P., Ruffenach F., Joint M., Anheim M., Martinez-Cerdeno V., Tassone F., Willemsen R., Hukema R.K., Viville S., Martinat C., Todd P.K., Charlet-Berguerand N. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome. Neuron. 2017. 93(2): 331–347.

  113. Sellier C., Usdin K., Pastori C., Peschansky V.J., Tassone F., Charlet-Berguerand N. The multiple molecular facets of fragile X-associated tremor/ataxia syndrome. J Neurodev. Disord. 2014. 6(1): 23.

  114. Sharma A., Hoeffer C.A., Takayasu Y., Miyawaki T., McBride S.M., Klann E., Zukin R.S. Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 2010. 30(2): 694–702.

  115. Shelton A.L., Cornish K.M., Godler D., Bui Q.M., Kolbe S., Fielding J. White matter microstructure, cognition, and molecular markers in fragile X premutation females. Neurology. 2017. 88(22): 2080–2088.

  116. Sherman S.L. Premature ovarian failure in the fragile X syndrome. Am. J. Med. Genet. 2000. 97(3): 189–194.

  117. Sterling A., Abbeduto L. Language development in school-age girls with fragile X syndrome. Journal of Intellectual Disability Research. 2012. 56(10): 974–983.

  118. Stöger R., Genereux D.P., Hagerman R.J., Hagerman P.J., Tassone F., Laird C.D. Testing the FMR1 promoter for mosaicism in DNA methylation among CpG sites, strands, and cells in FMR1-expressing males with fragile X syndrome. PLoS One. 2011. 6(8): e23648.

  119. Sullivan A.K., Marcus M., Epstein M.P., Allen E.G., Anido A.E., Paquin J.J., Yadav-Shah M., Sherman S.L. Association of FMR1 repeat size with ovarian dysfunction. Hum. Reprod. 2005. 20: 402–412.

  120. Tassone F., Hagerman R.J., Chamberlain W.D., Hagerman P.J. Transcription of the FMR1 gene in individuals with fragile X syndrome. Am. J. Med. Genet. 2000. 97(3): 195–203.

  121. Tassone F., Beilina A., Carosi C., Albertosi S., Bagni C., Li L., Glover K., Bentley D., Hagerman P.J. Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA. 2007. 13(4): 555–562.

  122. Tassone F., Hagerman R.J., Taylor A.K., Hagerman P.J. A majority of fragile X males with methylated, full mutation alleles have significant levels of FMR1 messenger RNA. J. Med. Genet. 2001. 38(7): 453–456.

  123. Tassone F., Iwahashi C., Hagerman P.J. FMR1 RNA within the intranuclear inclusions of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). RNA Biology. 2004. 1(2): 103–105.

  124. Tassone F., Iong K.P., Tong T.H., Lo J., Gane L.W., Berry-Kravis E., Nguyen D., Mu L.Y., Laffin J., Bailey D.B., Hagerman R.J. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med. 2012. 21.4(12): 100. https://doi.org/10.1186/gm401

  125. Todd P.K., Oh S.Y., Krans A., He F., Sellier C., Frazer M., Renoux A.J., Chen K.C., Scaglione K.M., Basrur V., Elenitoba-Johnson K., Vonsattel J.P., Louis E.D., Sutton M.A., Taylor J.P., Mills R.E., Charlet-Berguerand N., Paulson H.L. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron. 2013. 78(3): 440–455.

  126. Villate O., Ibarluzea N., Maortua H., de la Hoz A.B., Rodriguez-Revenga L., Izquierdo-Álvarez S., Tejada M.I. Effect of AGG Interruptions on FMR1 Maternal Transmissions. Front. Mol. Biosci. 2020. 7: 135.

  127. Welt C.K., Smith P.C., Taylor A.E. Evidence of early ovarian aging in fragile X premutation carriers. J. Clin. Endocrinol. Metab. 2004. 89(9): 4569–4574.

  128. Wheeler A.C., Sideris J., Hagerman R., Berry-Kravis E., Tassone F., Bailey D.B. Jr. Developmental profiles of infants with an FMR1 premutation. J Neurodev Disord. 2016. 8(40). https://doi.org/10.1186/s11689-016-9171-8

  129. Westmark C.J., Sokol D.K., Maloney B., Lahiri D.K. Novel roles of amyloid-beta precursor protein metabolites in fragile X syndrome and autism. Mol. Psychiatry. 2016. 21(10): 1333–1341.

Дополнительные материалы отсутствуют.