Subscribe to RSS
DOI: 10.1055/s-2001-15398
Skewed X Inactivation in X-Linked Disorders
Publication History
Publication Date:
31 December 2001 (online)
![](https://www.thieme-connect.de/media/srm/200102/lookinside/thumbnails/10.1055-s-2001-15398-1.jpg)
ABSTRACT
X chromosome inactivation is a process by which the dosage of proteins transcribed from genes on the X chromosome is equalized between males (XY) and females (XX) through the silencing of most genes on one of the two X chromosomes in females. Although the choice of which of the two X's is inactivated is entirely random, not all women have a 50:50 ratio of cells with one or the other X chromosomes active. A number of different mechanisms lead to extremely skewed ratios and this can result in expression of the phenotype of X-linked recessive disorders in females. Nonrandom X inactivation patterns are also associated with selective female survival in male-lethal X-linked dominant disorders or with variable severity of the phenotype in women carrying X-linked dominant mutations. These features are important for the study and gene identification of X-linked disorders and for counseling of affected families.
KEYWORD
X-linked disorders - X inactivation - skewed
REFERENCES
- 1 Lyon M F. Gene action in the X-chromosome of the mouse (Mus musculus L). Nature . 1961; 190 372-373
- 2 Heard E, Clerc P, Avner P. X-chromosome inactivation in mammals. Annu Rev Genet . 1997; 31 571-610
- 3 Monk M, Boubelik M, Lehnert S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development . 1987; 99 371-382
- 4 Kay G F, Barton S C, Surani M A, Rastan S. Imprinting and X chromosome counting mechanisms determine Xist expression in early mouse development. Cell . 1994; 77 639-650
- 5 Clemson C M, McNeil J A, Willard H F, Lawrence J B. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J Cell Biol . 1996; 132 259-275
- 6 Borsani G, Tonlorenzi R, Simmler M C. Characterization of a murine gene expressed from the inactive X chromosome. Nature . 1991; 351 325-329
- 7 Brown C J, Ballabio A, Rupert J L. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature . 1991; 349 38-44
- 8 Norris D P, Brockdorff N, Rastan S. Methylation status of CpG-rich islands on active and inactive mouse X chromosomes. Mamm Genome . 1991; 1 78-83
- 9 Jeppesen P, Turner B M. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell . 1993; 74 281-289
- 10 Costanzi C, Pehrson J R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature . 1998; 393 599-601
- 11 Carrel L, Cottle A A, Goglin K C, Willard H F. A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci U S A . 1999; 96 14440-14444
- 12 Willard H F. The sex chromosomes and X chromosome inactivation. In: Scriver CR, Beaudet AL, eds. The Metabolic and Molecular Bases of Inherited Disease 7th ed. New York: McGraw-Hill 1995: 719-737
- 13 Schanen C, Francke U. A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map. Am J Hum Genet . 1998; 63 267-269
- 14 Schanen N C, Kurczynski T W, Brunelle D, Woodcock M M, Dure L S, Percy A K. Neonatal encephalopathy in two boys in families with recurrent Rett syndrome. J Child Neurol . 1998; 13 229-231
- 15 Roberts J L, Morrow B, Vega-Rich C, Salafia C M, Nitowsky H M. Incontinentia pigmenti in a newborn male infant with DNA confirmation. Am J Med Genet . 1998; 75 159-163
- 16 Smahi A, Courtois G, Vabres P. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature . 2000; 405 466-472
- 17 Pegoraro E, Whitaker J, Mowery-Rushton P, Surti U, Lanasa M, Hoffman E P. Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28. Am J Hum Genet . 1997; 61 160-170
- 18 Sangha K K, Stephenson M D, Brown C J, Robinson W P. Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion. Am J Hum Genet . 1999; 65 913-917
- 19 Lanasa M C, Hogge W A, Hoffman E P. Sex Chromosome Genetics '99. The X chromosome and recurrent spontaneous abortion: the significance of transmanifesting carriers. Am J Hum Genet . 1999; 64 934-938
- 20 Bacino C A, Stockton D W, Sierra R A, Heilstedt H A, Lewandowski R, Van den Veyver B I. Terminal osseous dysplasia and pigmentary defects: clinical characterization of a novel male lethal X-linked syndrome. Am J Med Genet . 2000; 94 102-112
- 21 Lindsay E A, Grillo A, Ferrero G B. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization. Am J Med Genet . 1994; 49 229-234
- 22 Migeon B R, Axelman J, de Beur J S, Valle D, Mitchell G A, Rosenbaum K N. Selection against lethal alleles in females heterozygous for incontinentia pigmenti. Am J Hum Genet . 1989; 44 100-106
- 23 Wieacker P, Zimmer J, Ropers H H. X inactivation patterns in two syndromes with probable X-linked dominant, male lethal inheritance. Clin Genet . 1985; 28 238-242
- 24 Hoag H M, Taylor S A, Duncan A M, Khalifa M M. Evidence that skewed X inactivation is not needed for the phenotypic expression of Aicardi syndrome. Hum Genet . 1997; 100 459-464
- 25 Wechsler M A, Papa C M, Haberman F, Marion R W. Variable expression in focal dermal hypoplasia: an example of differential X-chromosome inactivation. Am J Dis Child . 1988; 142 297-300
- 26 Gorski J L. Father-to-daughter transmission of focal dermal hypoplasia associated with nonrandom X-inactivation: support for X-linked inheritance and paternal X chromosome mosaicism. Am J Med Genet . 1991; 40 332-337
- 27 Zoghbi H Y, Percy A K, Schultz R J, Fill C. Patterns of X chromosome inactivation in the Rett syndrome. Brain Dev . 1990; 12 131-135
- 28 Sirianni N, Naidu S, Pereira J, Pillotto R F, Hoffman E P. Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am J Hum Genet . 1998; 63 1552-1558
- 29 Amir R E, Van den Veyver B I, Schultz R. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol . 2000; 47 670-679
- 30 Belmont J W. Genetic control of X inactivation and processes leading to X- inactivation skewing. Am J Hum Genet . 1996; 58 1101-1108
- 31 Zhang W, Amir R, Stockton D W, Van den Veyver B I, Bacino C A, Zoghbi H Y. Terminal osseous dysplasia with pigmentary defects maps to human chromosome Xq27.3-xqter. Am J Hum Genet . 2000; 66 1461-1464
- 32 Allen R C, Nachtman R G, Rosenblatt H M, Belmont J W. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia. Am J Hum Genet . 1994; 54 25-35
- 33 de Saint Basile G, Notarangelo L D, Bonaiti-Pellie C. Wiskott-Aldrich syndrome carrier detection with the hypervariable marker M27 beta. Hum Genet . 1992; 89 223-228
- 34 Vogelstein B, Fearon E R, Hamilton S R, Feinberg A P. Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. Science . 1985; 227 642-645
- 35 Vogelstein B, Fearon E R, Hamilton S R. Clonal analysis using recombinant DNA probes from the X-chromosome. Cancer Res . 1987; 47 4806-4813
- 36 Prchal J T, Guan Y L. A novel clonality assay based on transcriptional analysis of the active X chromosome. Stem Cells (suppl 1). 1993; 11 (62-65)
- 37 Liu Y, Phelan J, Go R C, Prchal J F, Prchal J T. Rapid determination of clonality by detection of two closely-linked X chromosome exonic polymorphisms using allele-specific PCR. J Clin Invest . 1997; 99 1984-1990
- 38 Keith D H, Singer-Sam J, Riggs A D. Active X chromosome DNA is unmethylated at eight CCGG sites clustered in a guanine-plus-cytosine-rich island at the 5′ end of the gene for phosphoglycerate kinase. Mol Cell Biol . 1986; 6 4122-4125
- 39 Boyd Y, Fraser N J. Methylation patterns at the hypervariable X-chromosome locus DXS255 (M27 beta): correlation with X-inactivation status. Genomics . 1990; 7 182-187
- 40 Fey M F, Liechti-Gallati S, von Rohr A. Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood . 1994; 83 931-938
- 41 Allen R C, Zoghbi H Y, Moseley A B, Rosenblatt H M, Belmont J W. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet . 1992; 51 1229-1239
- 42 Naumova A K, Plenge R M, Bird L M. Heritability of X-chromosome-inactivation phenotype in a large family. Am J Hum Genet . 1996; 58 1111-1119
- 43 Kubota T, Nonoyama S, Tonoki H. A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR. Hum Genet . 1999; 104 49-55
- 44 Sharp A, Robinson D. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet . 2000; 107 343-349
- 45 Monteiro J, Derom C, Vlietinck R, Kohn N, Lesser M, Gregersen P K. Commitment to X inactivation precedes the twinning event in monochorionic MZ twins. Am J Hum Genet . 1998; 63 339-346
- 46 Carrel L, Willard H F. An assay for X inactivation based on differential methylation at the fragile X locus, FMR1. Am J Med Genet . 1996; 64 27-30
- 47 Gartler S M, Gandini E, Angioni G, Argiolas N. Glucose-6 phosphate dehydrogenase mosaicism: utilization as a tracer in the study of the development of hair root cells. Ann Hum Genet . 1969; 33 171-176
- 48 Fialkow P J. Primordial cell pool size and lineage relationships of five human cell types. Ann Hum Genet . 1973; 37 39-48
- 49 Gregg X T, Kralovics R, Prchal J T. A polymorphism of the X-linked gene IDS increases the number of females informative for transcriptional clonality assays. Am J Hematol . 2000; 63 184-191
- 50 Ellison K A, Fill C P, Terwilliger J. Examination of X chromosome markers in Rett syndrome: exclusion mapping with a novel variation on multilocus linkage analysis. Am J Hum Genet . 1992; 50 278-287
- 51 Boggs B A, Chinault A C. Analysis of replication timing properties of human X-chromosomal loci by fluorescence in situ hybridization. Proc Natl Acad Sci U S A . 1994; 91 6083-6087
- 52 Busque L, Mio R, Mattioli J. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood . 1996; 88 59-65
- 53 Lanasa M C, Hogge W A, Kubik C, Blancato J, Hoffman E P. Highly skewed X-chromosome inactivation is associated with idiopathic recurrent spontaneous abortion. Am J Hum Genet . 1999; 65 252-254
- 54 Azofeifa J, Voit T, Hubner C, Cremer M. X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum Genet . 1995; 96 167-176
- 55 Plenge R M, Hendrich B D, Schwartz C. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat Genet . 1997; 17 353-356
- 56 Naumova A K, Olien L, Bird L M. Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human. Eur J Hum Genet . 1998; 6 552-562
- 57 Parolini O, Ressmann G, Haas O A. X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med . 1998; 338 291-295
- 58 Orstavik K H, Orstavik R E, Schwartz M. Skewed X chromosome inactivation in a female with haemophilia B and in her non-carrier daughter: a genetic influence on X chromosome inactivation?. J Med Genet . 1999; 36 865-866
- 59 Lee J T. Disruption of imprinted X inactivation by parent-of-origin effects at Tsix Cell . 2000; 103 17-27
- 60 Puck J M, Willard H F. X inactivation in females with X-linked disease. N Engl J Med . 1998; 338 325-328
- 61 Mattei M G, Mattei J F, Ayme S, Giraud F. X-autosome translocations: cytogenetic characteristics and their consequences. Hum Genet . 1982; 61 295-309
- 62 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. Am J Med Genet . 1992; 42 161-169
- 63 White W M, Willard H F, Van Dyke L D, Wolff D J. The spreading of X inactivation into autosomal material of an X/autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA. Am J Hum Genet . 1998; 63 20-28
- 64 Lyon M F. X-chromosome inactivation spreads itself: effects in autosomes. Am J Hum Genet . 1998; 63 17-19
- 65 Boyd Y, Buckle V, Holt S, Munro E, Hunter D, Craig I. Muscular dystrophy in girls with X/autosome translocations. J Med Genet . 1986; 23 484-490
- 66 Mandel J L, Monaco A P, Nelson D L, Schlessinger D, Willard H. Genome analysis and the human X chromosome. Science . 1992; 258 103-109
- 67 Goodship J, Carter J, Espanol T, Boyd Y, Malcolm S, Levinsky R J. Carrier detection in Wiskott-Aldrich syndrome: combined use of M27 beta for X-inactivation studies and as a linked probe. Blood . 1991; 77 2677-2681
- 68 Puck J M, Stewart C C, Nussbaum R L. Maximum-likelihood analysis of human T-cell X chromosome inactivation patterns: normal women versus carriers of X-linked severe combined immunodeficiency. Am J Hum Genet . 1992; 50 742-748
- 69 Migeon B R, Moser H W, Moser A B, Axelman J, Sillence D, Norum R A. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proc Natl Acad Sci U S A . 1981; 78 5066-5070
- 70 Cotter P D, May A, Fitzsimons E J. Late-onset X-linked sideroblastic anemia: missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest . 1995; 96 2090-2096
- 71 Richards C S, Watkins S C, Hoffman E P. Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy. Am J Hum Genet . 1990; 46 672-681
- 72 Lupski J R, Garcia C A, Zoghbi H Y, Hoffman E P, Fenwick R G. Discordance of muscular dystrophy in monozygotic female twins: evidence supporting asymmetric splitting of the inner cell mass in a manifesting carrier of Duchenne dystrophy. Am J Med Genet . 1991; 40 354-364
- 73 Winchester B, Young E, Geddes S. Female twin with Hunter disease due to nonrandom inactivation of the X- chromosome: a consequence of twinning. Am J Med Genet . 1992; 44 834-838
- 74 Redonnet-Vernhet I, Ploos van Amstel K J, Jansen R P, Wevers R A, Salvayre R, Levade T. Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene. J Med Genet . 1996; 33 682-688
- 75 Costa T, Greer W, Rysiecki G, Buncic J R, Ray P N. Monozygotic twins discordant for Aicardi syndrome. J Med Genet . 1997; 34 688-691
- 76 Puck J M. The timing of twinning: more insights from X inactivation. Am J Hum Genet . 1998; 63 327-328
- 77 Fisk N M, Howard C, Ware M, Bennett P R. X-chromosome inactivation patterns do not implicate asymmetric splitting of the inner cell mass in the aetiology of twin-twin transfusion syndrome. Mol Hum Reprod . 1999; 5 52-56
- 78 Traupe H. Functional X-chromosomal mosaicism of the skin: Rudolf Happle and the lines of Alfred Blaschko. Am J Med Genet . 1999; 85 324-329
- 79 Moss C. Cytogenetic and molecular evidence for cutaneous mosaicism: the ectodermal origin of Blaschko lines. Am J Med Genet . 1999; 85 330-333
- 80 Rott H D. Extracutaneous analogies of Blaschko lines. Am J Med Genet . 1999; 85 338-341
- 81 Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann Neurol . 1983; 14 471-479
- 82 Amir R E, Van den Veyver B I, Wan M, Tran C Q, Francke U, Zoghbi H Y. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet . 1999; 23 185-188
- 83 Camus P, Abbadi N, Gilgenkrantz S. X inactivation in Rett syndrome: a preliminary study showing partial preferential inactivation of paternal X with the M27 beta probe. Am J Med Genet . 1994; 50 307-308
- 84 Migeon B R, Dunn M A, Thomas G, Schmeckpeper B J, Naidu S. Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosome is not involved in Rett syndrome. Am J Hum Genet . 1995; 56 647-653
- 85 Parrish J E, Scheuerle A E, Lewis R A, Levy M L, Nelson D L. Selection against mutant alleles in blood leukocytes is a consistent feature in incontinentia pigmenti type 2. Hum Mol Genet . 1996; 5 1777-1783
- 86 Zonana J, Elder M E, Schneider L C. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet . 2000; 67 1555-1562
- 87 Wapenaar M C, Bassi M T, Schaefer L. The genes for X-linked ocular albinism (OA1) and microphthalmia with linear skin defects (MLS): cloning and characterization of the critical regions. Hum Mol Genet . 1993; 2 947-952
- 88 Ropers H H, Zuffardi O, Bianchi E, Tiepolo L. Agenesis of corpus callosum, ocular, and skeletal anomalies (X-linked dominant Aicardi's syndrome) in a girl with balanced X/3 translocation. Hum Genet . 1982; 61 364-368
- 89 Neidich J A, Nussbaum R L, Packer R J, Emanuel B S, Puck J M. Heterogeneity of clinical severity and molecular lesions in Aicardi syndrome. J Pediatr . 1990; 116 911-917