The Relationship betweenSkewed X-chromosome Inactivation and Neurological Disorders Development: A Review
International Clinical Neuroscience Journal,
Vol. 3 No. 2 (2016),
22 September 2016
X-chromosome inactivation (XCI) is a process by which one of the copies of the X chromosome in mammalian female cells is inactivated. The XCI causes a balanced X-linked gene quantity between male and females; moreover, it results mosaic females which have paternal active X in some cells and maternal active X in others. Cellular mosaicism is a noteworthy phenomenon and lowers the risk of X-linked diseases in women because the presentation of a mutation on both X chromosomes is unlikely. Therefore, in heterozygous females, the XCI will be present only on the half of the X genome. In contrast, a similar mutation will present in all of the cells of men.Female carriers of some neurological disorders such as autism, Rett syndrome, adreno-leukodystrophyand X-linked mental retardation are reported to present XCI. These observations underscore the important role of X chromosome in the brain which may be related to the existence of a chromosomal signature of gene expression associated with the X-chromosome for neurological conditions not normally associated with that chromosome.In this review, we focused on latestinvestigations on the role of XCI in neurodevelopmental disorders and how these investigations can be effective in the treatment of neurodevelopmental disorders.
- Rett Syndrome
- X Chromosome Inactivation
- X-linked mental retardation
How to Cite
Yen ZC, Meyer IM, Karalic S, Brown CJ. A cross-species comparison of X-chromosome inactivation in Eutheria. Genomics. 2007;90(4):453-63.
Willard H, Brown C, Carrel L, Hendrich B, Miller A, editors. Epigenetic and chromosomal control of gene expression: molecular and genetic analysis of X chromosome inactivation. Cold Spring Harbor symposia on quantitative biology; 1993: Cold Spring Harbor Laboratory Press.
Yang C, Chapman AG, Kelsey AD, Minks J, Cotton AM, Brown CJ. X-chromosome inactivation: molecular mechanisms from the human perspective. Human genetics. 2011;130(2):175-85.
Minks J, Robinson WP, Brown CJ. A skewed view of X chromosome inactivation. The Journal of clinical investigation. 2007;118(1).
Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J, et al. X Chromosome–Inactivation Patterns of 1,005 Phenotypically Unaffected Females. The American Journal of Human Genetics. 2006;79(3):493-9.
Muers MR, Sharpe JA, Garrick D, Sloane-Stanley J, Nolan PM, Hacker T, et al. Defining the cause of skewed X-chromosome inactivation in X-linked mental retardation by use of a mouse model. The American Journal of Human Genetics. 2007;80(6):1138-49.
Migeon BR. Why females are mosaics, X-chromosome inactivation, and sex differences in disease. Gender medicine. 2007;4(2):97-105.
Wang Z, Yan A, Lin Y, Xie H, Zhou C, Lan F. Familial skewed x chromosome inactivation in adrenoleukodystrophy manifesting heterozygotes from a chinese pedigree. PloS one. 2013;8(3):e57977.
Pugacheva EM, Tiwari VK, Abdullaev Z, Vostrov AA, Flanagan PT, Quitschke WW, et al. Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. Human molecular genetics. 2005;14(7):953-65.
Jeon Y, Sarma K, Lee JT. New and Xisting regulatory mechanisms of X chromosome inactivation. Current opinion in genetics & development. 2012;22(2):62-71.
Barakat TS, Jonkers I, Monkhorst K, Gribnau J. X-changing information on X inactivation. Experimental cell research. 2010;316(5):679-87.
Cattanach B, Isaacson J. Controlling elements in the mouse X chromosome. Genetics. 1967;57(2):331.
Tomkins DJ, McDonald HL, Farrell SA, Brown CJ. Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay. European Journal of Human Genetics. 2002;10(1):44-51.
Salsano E, Tabano S, Sirchia SM, Colapietro P, Castellotti B, Gellera C, et al. Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms. Orphanet journal of rare diseases. 2012;7(1):1.
Bolduc V, Chagnon P, Provost S, Dubé M-P, Belisle C, Gingras M, et al. No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans. The Journal of clinical investigation. 2008;118(1):333-41.
Sharp AJ, Spotswood HT, Robinson DO, Turner BM, Jacobs PA. Molecular and cytogenetic analysis of the spreading of X inactivation in X; autosome translocations. Human molecular genetics. 2002;11(25):3145-56.
Schmidt M, Du Sart D. Functional disomies of the X chromosome influence the cell selection and hence the X inactivation pattern in females with balanced X‐autosome translocations: a review of 122 cases. American journal of medical genetics. 1992;42(2):161-9.
Jacobs PA, Hunt PA, Mayer M, Bart RD. Duchenne muscular dystrophy (DMD) in a female with an X/autosomal translocation: Further evidence that the DMD locus is at Xp21. American journal of human genetics. 1981;33(4):513.
Solari A, Rahn I, Ferreyra M, Carballo M. The behavior of sex chromosomes in two human X-autosome translocations: failure of extensive X-inactivation spreading. Biocell: official journal of the Sociedades Latinoamericanas de Microscopia Electronica et al. 2001;25(2):155-66.
Caiulo A, Bardoni B, Camerino G, Guioli S, Minelli A, Piantanida M, et al. Cytogenetic and molecular analysis of an unbalanced translocation (X; 7)(q28; p15) in a dysmorphic girl. Human genetics. 1989;84(1):51-4.
Hall LL, Clemson CM, Byron M, Wydner K, Lawrence JB. Unbalanced X; autosome translocations provide evidence for sequence specificity in the association of XIST RNA with chromatin. Human molecular genetics. 2002;11(25):3157-65.
Gartler SM, Riggs AD. Mammalian X-chromosome inactivation. Annual review of genetics. 1983;17(1):155-90.
Lyon MF. X-chromosome inactivation: a repeat hypothesis. Cytogenetic and Genome Research. 1998;80(1-4):133-7.
Wang Z, Willard HF, Mukherjee S, Furey TS. Evidence of influence of genomic DNA sequence on human X chromosome inactivation. PLoS Comput Biol. 2006;2(9):e113.
Gartler SM, Goldman MA. Biology of the X chromosome. Current opinion in pediatrics. 2001;13(4):340-5.
Bittel DC, Theodoro MF, Kibiryeva N, Fischer W, Talebizadeh Z, Butler MG. Comparison of X-chromosome inactivation patterns in multiple tissues from human females. Journal of medical genetics. 2008;45(5):309-13.
Mitchell AC, Mirnics K. Gene expression profiling of the brain: pondering facts and fiction. Neurobiology of disease. 2012;45(1):3-7.
Laumonnier F, Cuthbert PC, Grant SG. The role of neuronal complexes in human X-linked brain diseases. The American Journal of Human Genetics. 2007;80(2):205-20.
Disteche CM. High expression of the mammalian X chromosome in brain. Brain research. 2006;1126(1):46-9.
Disteche CM. Dosage compensation of the active X chromosome in mammals. Nature genetics. 2006;38(1):47-53.
Straub T, Becker PB. Dosage compensation: the beginning and end of generalization. Nature Reviews Genetics. 2007;8(1):47-57.
Deng X, Hiatt JB, Ercan S, Sturgill D, Hillier LW, Schlesinger F, et al. Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nature genetics. 2011;43(12):1179-85.
Kharchenko PV, Xi R, Park PJ. Evidence for dosage compensation between the X chromosome and autosomes in mammals. Nature genetics. 2011;43(12):1167-9.
Oostra B, Willemsen R. The X chromosome and fragile X mental retardation. Cytogenetic and genome research. 2003;99(1-4):257-64.
Chadwick LH, Wade PA. MeCP2 in Rett syndrome: transcriptional repressor or chromatin architectural protein? Current opinion in genetics & development. 2007;17(2):121-5.
Zanni G, Bertini ES. X-linked disorders with cerebellar dysgenesis. Orphanet journal of rare diseases. 2011;6(1):1.
Migeon BR. The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases. Jama. 2006;295(12):1428-33.
Kristiansen M, Langerød A, Knudsen G, Weber B, Børresen-Dale A, Ørstavik K. High frequency of skewed X inactivation in young breast cancer patients. Journal of medical genetics. 2002;39(1):30-3.
Bicocchi MP, Migeon BR, Pasino M, Lanza T, Bottini F, Boeri E, et al. Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A. European journal of human genetics. 2005;13(5):635-40.
Knudsen GPS, Neilson TC, Pedersen J, Kerr A, Schwartz M, Hulten M, et al. Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers. European journal of human genetics. 2006;14(11):1189-94.
Talebizadeh Z, Bittel D, Veatch O, Kibiryeva N, Butler M. Brief report: non-random X chromosome inactivation in females with autism. Journal of autism and developmental disorders. 2005;35(5):675-81.
Plenge RM, Stevenson RA, Lubs HA, Schwartz CE, Willard HF. Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders. The American Journal of Human Genetics. 2002;71(1):168-73.
Blaw M. Melanodermic type leukodystrophy (adrenoleukodystrophy). Handbook of clinical neurology. 1970;10:128-33.
GRIFFIN JW, GOREN E, SCHAUMBURG H, Engel WK, LORIAUX L. Adrenomyeloneuropathy A probable variant of adrenoleukodystrophy I. Clinical and endocrinologic aspects. Neurology. 1977;27(12):1107-.
Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, et al. Inheritance of most X‐linked traits is not dominant or recessive, just X‐linked. American journal of medical genetics Part A. 2004;129(2):136-43.
Restuccia D, Di Lazzaro V, Valeriani M, Oliviero A, Le Pera D, Colosimo C, et al. Neurophysiological abnormalities in adrenoleukodystrophy carriers. Evidence of different degrees of central nervous system involvement. Brain. 1997;120(7):1139-48.
Bezman L, Moser AB, Raymond GV, Rinaldo P, Watkins PA, Smith KD, et al. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Annals of neurology. 2001;49(4):512-7.
Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, et al. ABCD1 mutations and the X‐linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations. Human mutation. 2001;18(6):499-515.
Migeon BR, Moser HW, Moser AB, Axelman J, Sillence D, Norum RA. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proceedings of the National Academy of Sciences. 1981;78(8):5066-70.
Oberle I, Drayna D, Camerino G, White R, Mandel J-L. The telomeric region of the human X chromosome long arm: presence of a highly polymorphic DNA marker and analysis of recombination frequency. Proceedings of the National Academy of Sciences. 1985;82(9):2824-8.
Aubourg PR, Sack GH, Meyers DA, Lease JJ, Moser HW. Linkage of adrenoleukodystrophy to a polymorphic DNA probe. Annals of neurology. 1987;21(4):349-52.
Dvorakova L, Storkanova G, Unterrainer G, Hujová J, Kmoch S, Zeman J, et al. Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acid exchange. Human mutation. 2001;18(1):52.
Berger J, Molzer B, Fae I, Bernheimer H. X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes. Biochemical and biophysical research communications. 1994;205(3):1638-43.
Smith KD, Kemp S, Braiterman LT, Lu J-F, Wei H-M, Geraghty M, et al. X-linked adrenoleukodystrophy: genes, mutations, and phenotypes. Neurochemical research. 1999;24(4):521-35.
Kemp S, Ligtenberg MJ, Vangeel BM, Barth PG, Wolterman RA, Schoute F, et al. Identification of a two base pair deletion in five unrelated families with adrenoleukodystrophy: a possible hot spot for mutations. Biochemical and biophysical research communications. 1994;202(2):647-53.
Korenke GC, Wilichowski E, Hunneman DH, Hanefeld F, Fuchs S, Krasemann E, et al. Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype. Annals of neurology. 1996;40(2):254-7.
Yatsenko A, Shroyer N, Lewis R, Lupski J. Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4). Human genetics. 2001;108(4):346-55.
Kok F, Neumann S, Sarde CO, Zheng S, Wu KH, Wei HM, et al. Mutational analysis of patients with X‐linked adrenoleukodystrophy. Human mutation. 1995;6(2):104-15.
Eichler EE, Budarf ML, Rocchi M, Deaven LL, Doggett NA, Baldini A, et al. Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity. Human molecular genetics. 1997;6(7):991-1002.
Antonarakis S, Van Aelst L. Mind the GAP, Rho, Rab and GDI. Nature genetics. 1998;19(2):106-8.
Gedeon AK, Donnelly AJ, Mulley JC, Kerr B, Turner G. Letter to the editor: How many X‐linked genes for non‐specific mental retardation (MRX) are there? American journal of medical genetics. 1996;64(1):158-62.
Nobes CD, Hall A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell. 1995;81(1):53-62.
Kaufmann N, Wills ZP, Van Vactor D. Drosophila Rac1 controls motor axon guidance. Development. 1998;125(3):453-61.
Luo L, Jan LY, Jan Y-N. Rho family small GTP-binding proteins in growth cone signalling. Current opinion in neurobiology. 1997;7(1):81-6.
Threadgill R, Bobb K, Ghosh A. Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron. 1997;19(3):625-34.
Gu XX, Decorte R, Marynen P, Fryns J-P, Cassiman J-J, Raeymaekers P. Localisation of a new gene for non-specific mental retardation to Xq22-q26 (MRX35). Journal of medical genetics. 1996;33(1):52-5.
Ryan SG, Chance PF, Zou C-H, Spinner NB, Golden JA, Smietana S. Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing. Nature genetics. 1997;17(1):92-5.
Chen LY, Rex CS, Babayan AH, Kramár EA, Lynch G, Gall CM, et al. Physiological activation of synaptic Rac> PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome. The Journal of Neuroscience. 2010;30(33):10977-84.
Hayashi ML, Rao BS, Seo J-S, Choi H-S, Dolan BM, Choi S-Y, et al. Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proceedings of the national academy of sciences. 2007;104(27):11489-94.
Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL, et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. The American Journal of Human Genetics. 2009;85(4):503-14.
Peprah E. Fragile X syndrome: the FMR1 CGG repeat distribution among world populations. Annals of human genetics. 2012;76(2):178-91.
Verkerk AJ, Pieretti M, Sutcliffe JS, Fu Y-H, Kuhl DP, Pizzuti A, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65(5):905-14.
Ma Q-L, Yang F, Frautschy SA, Cole GM. PAK in Alzheimer disease, Huntington disease and X-linked mental retardation. Cellular logistics. 2012;2(2):117-25.
Bassell GJ, Warren ST. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron. 2008;60(2):201-14.
De Rubeis S, Bagni C. Fragile X mental retardation protein control of neuronal mRNA metabolism: Insights into mRNA stability. Molecular and Cellular Neuroscience. 2010;43(1):43-50.
Bassell GJ, Gross C. Reducing glutamate signaling pays off in fragile X. Nature medicine. 2008;14(3):249-50.
Antar L, Dictenberg J, Plociniak M, Afroz R, Bassell G. Localization of FMRP‐associated mRNA granules and requirement of microtubules for activity‐dependent trafficking in hippocampal neurons. Genes, Brain and Behavior. 2005;4(6):350-9.
Baker K, Wray S, Ritter R, Mason S, Lanthorn T, Savelieva K. Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments. Genes, Brain and Behavior. 2010;9(6):562-74.
Mineur YS, Huynh LX, Crusio WE. Social behavior deficits in the Fmr1 mutant mouse. Behavioural brain research. 2006;168(1):172-5.
Peier AM, McIlwain KL, Kenneson A, Warren ST, Paylor R, Nelson DL. (Over) correction of FMR1 deficiency with YAC transgenics: behavioral and physical features. Human Molecular Genetics. 2000;9(8):1145-59.
Nomura Y. Early behavior characteristics and sleep disturbance in Rett syndrome. Brain and Development. 2005;27:S35-S42.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature genetics. 1999;23(2):185-8.
Trappe R, Laccone F, Cobilanschi J, Meins M, Huppke P, Hanefeld F, et al. MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. The American Journal of Human Genetics. 2001;68(5):1093-101.
Christodoulou J, Grimm A, Maher T, Bennetts B. RettBASE: the IRSA MECP2 variation database—a new mutation database in evolution. Human mutation. 2003;21(5):466-72.
Archer HL, Whatley SD, Evans JC, Ravine D, Huppke P, Kerr A, et al. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. Journal of medical genetics. 2006;43(5):451-6.
Pan H, Li MR, Nelson P, Bao XH, Wu XR, Yu S. Large deletions of the MECP2 gene in Chinese patients with classical Rett syndrome. Clinical genetics. 2006;70(5):418-9.
Smeets E, Terhal P, Casaer P, Peters A, Midro A, Schollen E, et al. Rett syndrome in females with CTS hot spot deletions: a disorder profile. American Journal of Medical Genetics Part A. 2005;132(2):117-20.
Neul J, Fang P, Barrish J, Lane J, Caeg E, Smith E, et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008;70(16):1313-21.
Kerr A, Archer H, Evans J, Prescott R, Gibbon F. People with MECP2 mutation‐positive Rett disorder who converse. Journal of Intellectual Disability Research. 2006;50(5):386-94.
Jorde LB, Hasstedt S, Ritvo E, Mason-Brothers A, Freeman B, Pingree C, et al. Complex segregation analysis of autism. American journal of human genetics. 1991;49(5):932.
Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychological medicine. 1995;25(01):63-77.
Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathies type I and II. Brain 1980; 103:259±280.
England JD, Garcia CA. Electrophysiological studies in the different genotypes of Charcot-Marie-Tooth disease. Curr Opin Neurol 1996;9:338±342.
McKusick, V. A. (1990). Mendelian Inheritance in Man (Baltimore: The Johns Hopkins UniversityPress).
Lupski JR, Montes de Oca-Luna R, Slaugenhaupt S, Pentao L, Guzzetta V, Trask BJ, Saucedo-Cardenas O, Barker DF, Killian JM, Garcia CA, Chakravarti A, Patel PI. DNA duplication as-sociated with Charcot-Marie-Tooth disease type 1A. Cell 1991; 66:219±232.
Vance, J. M., Barker, D., Yamaoka, L. H., Stajich, J. M., Loprest, L., Hung, W.-Y., Fischbeck, K., Roses, A. D., and Pericak-Vance, M. A. (1991). Localization of Charcot-Marie-Tooth disease type la (CMT la) to chromosome 17~11.2. Genomics 9, 623-628.
Nicholson G, Corbett A. Slowing of central conduction in X-linked Charcot-Marie-Tooth neuropathy shown by brainstem auditory evoked responses. J Neurol Neurosurg Psychiatry
Ionasescu W, Ionasescu R, Searby C. Screening of dominantly inherited Charcot-Marie-Tooth neuropathies. Muscle Nerve 1993;16:1232±1238.
Dermietzel R, Spray DC. Gap-junctions in the brain: where, what type, how many and why? Trends Neurosci 1993;16: 186 -192.
. Nicholson G, Nash J. Intermediate nerve conduction velocities define X-linked Charcot-Marie-Tooth neuropathy families. Neurology 1996;43:2558-2564.
- Abstract Viewed: 711 times
- PDF Downloaded: 669 times