Advertisement

Human Genetics

, Volume 135, Issue 7, pp 685–698 | Cite as

Determining the role of skewed X-chromosome inactivation in developing muscle symptoms in carriers of Duchenne muscular dystrophy

  • Emanuela Viggiano
  • Manuela Ergoli
  • Esther Picillo
  • Luisa Politano
Review

Abstract

Duchenne and Becker dystrophinopathies (DMD and BMD) are X-linked recessive disorders caused by mutations in the dystrophin gene that lead to absent or reduced expression of dystrophin in both skeletal and heart muscles. DMD/BMD female carriers are usually asymptomatic, although about 8 % may exhibit muscle or cardiac symptoms. Several mechanisms leading to a reduced dystrophin have been hypothesized to explain the clinical manifestations and, in particular, the role of the skewed XCI is questioned. In this review, the mechanism of XCI and its involvement in the phenotype of BMD/DMD carriers with both a normal karyotype or with X;autosome translocations with breakpoints at Xp21 (locus of the DMD gene) will be analyzed. We have previously observed that DMD carriers with moderate/severe muscle involvement, exhibit a moderate or extremely skewed XCI, in particular if presenting with an early onset of symptoms, while DMD carriers with mild muscle involvement present a random XCI. Moreover, we found that among 87.1 % of the carriers with X;autosome translocations involving the locus Xp21 who developed signs and symptoms of dystrophinopathy such as proximal muscle weakness, difficulty to run, jump and climb stairs, 95.2 % had a skewed XCI pattern in lymphocytes. These data support the hypothesis that skewed XCI is involved in the onset of phenotype in DMD carriers, the X chromosome carrying the normal DMD gene being preferentially inactivated and leading to a moderate–severe muscle involvement.

Keywords

Dyskeratosis Congenita Muscle Symptom Dystrophin Expression XIST Gene Autosome Translocation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank the patients and families for their cooperation. The samples analyzed were derived from the Naples Human Genetic BioBank that is part of Telethon Network of Genetic Biobanks and EuroBioBank. The financial support of Telethon (Project GTB12001H to LP) is acknowledged.

References

  1. Abbadi N, Philippe C, Chery M et al (1994) Additional case of female monozygotic twins discordant for the clinical manifestations of Duchenne muscular dystrophy due to opposite X-chromosome inactivation. Am J Med Genet 52:198–206. doi: 10.1002/ajmg.1320520215 PubMedCrossRefGoogle Scholar
  2. Abrams L, Cotter PD (2004) Prenatal diagnosis of de novo X;autosome translocations. Clin Genet 65:423–428. doi: 10.1111/j.0009-9163.2004.00255.x PubMedCrossRefGoogle Scholar
  3. Allen RC (1993) 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 51:1229–1239Google Scholar
  4. Amos-Landgraf JM, Cottle A, Plenge RM et al (2006) X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet 79:493–499PubMedPubMedCentralCrossRefGoogle Scholar
  5. Azofeifa J, Voit T, Hübner C, Cremer M (1995) 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 96:167–176PubMedCrossRefGoogle Scholar
  6. Bailey JA, Carrel L, Chakravarti A, Eichler EE (2000) Molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis. Proc Natl Acad Sci USA 97:6634–6639PubMedPubMedCentralCrossRefGoogle Scholar
  7. Barakat TS, Gunhanlar N, Pardo CG et al (2011) RNF12 activates Xist and is essential for X chromosome inactivation. PLoS Genet 7:e1002001. doi: 10.1371/journal.pgen.1002001 PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bicocchi MP, Migeon BR, Pasino M, Lanza T, Bottini F, Boeri E et al (2005) Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A. Eur J Hum Genet 13:635–640PubMedCrossRefGoogle Scholar
  9. Bittel DC, Theodoro MF, Kibiryeva N, Fischer W, Talebizadeh Z, Butler MG (2008) Comparison of X-chromosome inactivation patterns in multiple tissues from human females. J Med Genet 45:309–313PubMedCrossRefGoogle Scholar
  10. Bittner RE, Popoff I, Shorny S et al (1997) Dystrophin expression in heterozygous mdx/+ mice indicates imprinting of X chromosome inactivation by parent-of-origin-, tissue-, strain- and position-dependent factors. Anat Embryol 195:175–182PubMedCrossRefGoogle Scholar
  11. Bjerglund Nielsen L, Jacobsen BB, Nielsen IM, Tabor A (1983) X;autosome translocation in a girl with muscular dystrophy. Clin Genet 23:242Google Scholar
  12. Bodrug SE, Roberson JR, Weiss L et al (1990) Prenatal identification of a girl with a t(X;4)(p21;q35) translocation: molecular characterisation, paternal origin, and association with muscular dystrophy. J Med Genet 27:426–432PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bolduc V, Chagnon P, Provost S, Dubé M-P, Belisle C, Gingras M et al (2008) No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans J Clin Invest 118:333–341PubMedGoogle Scholar
  14. Boyd Y, Buckle V, Holt S et al (1986) Muscular dystrophy in girls with X;autosome translocations. J Med Genet 23:484–490PubMedPubMedCentralCrossRefGoogle Scholar
  15. Brioschi S, Gualandi F, Scotton C et al (2012) Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype. BMC Med Genet 13:73. doi: 10.1186/1471-2350-13-73 PubMedPubMedCentralCrossRefGoogle Scholar
  16. Brockdorff N, Ashworth A, Kay GF et al (1992) The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71:515–526PubMedCrossRefGoogle Scholar
  17. Brown CJ, Robinson WP (2000) The causes and consequences of random and non-random X chromosome inactivation in humans. Clin Genet 58:353–363PubMedCrossRefGoogle Scholar
  18. Brown CJ, Ballabio A, Rupert JL et al (1991) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349:38–44. doi: 10.1038/349038a0 PubMedCrossRefGoogle Scholar
  19. Brown CJ, Hendrich BD, Rupert JL et al (1992) The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71:527–542PubMedCrossRefGoogle Scholar
  20. Bushby KM, Goodship JA, Nicholson LV, Johnson MA, Haggerty ID, Gardner-Medwin D, Bushby KM, Goodship JA (1993) Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy. Neuromuscul Disord NMD 3:57–64. doi: 10.1016/0960-8966(93)90042-I PubMedCrossRefGoogle Scholar
  21. Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y et al (1996) Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88:59–65PubMedGoogle Scholar
  22. Calabrese JM, Sun W, Song L et al (2012) Site-specific silencing of regulatory elements as a mechanism of X inactivation. Cell 151:951–963. doi: 10.1016/j.cell.2012.10.037 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Canki N, Dutrillaux B, Tivadar I (1979) Dystrophie musculaire de Duchenne chez une petite fille porteuse d’une translocation t(X;3)(p21;ql3) de novo. Annales de génétique 22:35–39Google Scholar
  24. Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434:400–404. doi: 10.1038/nature03479 PubMedCrossRefGoogle Scholar
  25. Cattanach BM (1974) Position effect variegation in the mouse. Genet Res 23:291–306PubMedCrossRefGoogle Scholar
  26. Ceulemans BP, Storm K, Reyniers E Jr et al (2008) Muscle pain as the only presenting symptom in a girl with dystrophinopathy. Pediatr Neurol 38:64–66. doi: 10.1016/j.pediatrneurol.2007.09.006 PubMedCrossRefGoogle Scholar
  27. Chaumeil J, Le Baccon P, Wutz A, Heard E (2006) A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev 20:2223–2237. doi: 10.1101/gad.380906 PubMedPubMedCentralCrossRefGoogle Scholar
  28. Chelly J, Marlhens F, Marec BL et al (1986) De novo DNA microdeletion in a girl with Turner syndrome and Duchenne muscular dystrophy. Hum Genet 74:193–196. doi: 10.1007/BF00282093 PubMedCrossRefGoogle Scholar
  29. Christensen K, Kristiansen M, Hagen-Larsen H, Skytthe A, Bathum L, Jeune B et al (2000) X-linked genetic factors regulate hematopoietic stem-cell kinetics in females. Blood 95:2449–2451PubMedGoogle Scholar
  30. Chureau C, Chantalat S, Romito A et al (2011) Ftx is a non-coding RNA which affects Xist expression and chromatin structure within the X-inactivation center region. Hum Mol Genet 20:705–718. doi: 10.1093/hmg/ddq516 PubMedCrossRefGoogle Scholar
  31. Ciccodicola A, D’Esposito M, Esposito T et al (2000) Differentially regulated and evolved genes in the fully sequenced Xq/Yq pseudoautosomal region. Hum Mol Genet 9:395–401PubMedCrossRefGoogle Scholar
  32. Cohen DE, Davidow LS, Erwin JA et al (2007) The DXPas34 repeat regulates random and imprinted X inactivation. Dev Cell 12:57–71. doi: 10.1016/j.devcel.2006.11.014 PubMedCrossRefGoogle Scholar
  33. Comi LI, Nigro G, Politano L, Petretta VR (1992) The cardiomyopathy of Duchenne/Becker consultants. Int J Cardiol 34:297–305PubMedCrossRefGoogle Scholar
  34. Cotton AM, Chen C-Y, Lam LL et al (2014) Spread of X-chromosome inactivation into autosomal sequences: role for DNA elements, chromatin features and chromosomal domains. Hum Mol Genet 23:1211–1223. doi: 10.1093/hmg/ddt513 PubMedCrossRefGoogle Scholar
  35. Csankovszki G, Nagy A, Jaenisch R (2001) Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol 153:773–784PubMedPubMedCentralCrossRefGoogle Scholar
  36. Davie AM, Emery AE (1978) Estimation of proportion of new mutants among cases of Duchenne muscular dystrophy. J Med Genet 15:339–345PubMedPubMedCentralCrossRefGoogle Scholar
  37. Debrand E, Chureau C, Arnaud D et al (1999) Functional analysis of the DXPas34 locus, a 3′ regulator of Xist expression. Mol Cell Biol 19:8513–8525PubMedPubMedCentralCrossRefGoogle Scholar
  38. Devriendt K, Matthijs G, Legius E et al (1997) Skewed X-chromosome inactivation in female carriers of dyskeratosis congenita. Am J Hum Genet 60:581–587PubMedPubMedCentralGoogle Scholar
  39. Dixon JR, Selvaraj S, Yue F et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380. doi: 10.1038/nature11082 PubMedPubMedCentralCrossRefGoogle Scholar
  40. Doriguzzi C, Palmucci L, Mongini T et al (1999) Variable histological expression of dystrophinopathy in two females. Acta Neuropathol 97:657–660PubMedCrossRefGoogle Scholar
  41. Dubowitz V (1986) X;autosome translocations in females with Duchenne or Becker muscular dystrophy. Nature 322:291–292. doi: 10.1038/322291b0 PubMedCrossRefGoogle Scholar
  42. Dubowitz V (1995) Muscle disorders in childhood. Saunders, LondonGoogle Scholar
  43. Emanuel BS, Zackai EH, Tucker SH (1983) Further evidence for Xp21 location of Duchenne muscular dystrophy (DMD) locus: X;9 translocation in a female with DMD. J Med Genet 20:461–463PubMedPubMedCentralCrossRefGoogle Scholar
  44. Emery AE (1991) Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul Disord 1:19–29PubMedCrossRefGoogle Scholar
  45. Emery AE, Skinner R, Holloway S (1979) A study of possible heterogeneity in Duchenne muscular dystrophy. Clin Genet 15:444–449PubMedCrossRefGoogle Scholar
  46. Espinós C, Lorenzo JI, Casaña P et al (2000) Haemophilia B in a female caused by skewed inactivation of the normal X-chromosome. Haematologica 85:1092–1095PubMedGoogle Scholar
  47. Evans MI, Farrell SA, Greb A et al (1993) In utero fetal muscle biopsy for the diagnosis of Duchenne muscular dystrophy in a female fetus “suddenly at risk”. Am J Med Genet 46:309–312. doi: 10.1002/ajmg.1320460314 PubMedCrossRefGoogle Scholar
  48. Fey MF, Peter HJ, Hinds HL, Zimmermann A, Liechti-Gallati S, Gerber H et al (1992) Clonal analysis of human tumors with M27 beta, a highly informative polymorphic X chromosomal probe. J Clin Invest 89:1438–1444PubMedPubMedCentralCrossRefGoogle Scholar
  49. Fey MF, Liechti-Gallati S, von Rohr A, Borisch B, Theilkäs L, Schneider V et al (1994) Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood 83:931–938PubMedGoogle Scholar
  50. Fialkow PJ (1973) Primordial cell pool size and lineage relationships of five human cell types. Ann Hum Genet 37:39–48PubMedCrossRefGoogle Scholar
  51. Fidzianska A, Morrone A, Pegoraro E et al (1995) An X:autosome translocation stabilizes truncated dystrophin: implications for lack of truncated dystrophins in Duchenne muscular dystrophy. Neuropediatrics 26:163–167. doi: 10.1055/s-2007-979747 PubMedCrossRefGoogle Scholar
  52. Fujii K, Minami N, Hayashi Y et al (2009) Homozygous female Becker muscular dystrophy. Am J Med Genet 149A:1052–1055. doi: 10.1002/ajmg.a.32808 PubMedCrossRefGoogle Scholar
  53. Gaál M, László J (1977) X inactivation pattern in an unbalanced X-autosome translocation with gonadal dysgenesis. Hum Hered 27:396–402PubMedCrossRefGoogle Scholar
  54. Gale RE, Wheadon H, Linch DC (1991) X-chromosome inactivation patterns using HPRT and PGK polymorphisms in haematologically normal and post-chemotherapy females. Br J Haematol 79:193–197PubMedCrossRefGoogle Scholar
  55. Gale RE, Fielding AK, Harrison CN, Linch DC (1997) Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age. Br J Haematol 98:512–519PubMedCrossRefGoogle Scholar
  56. Gartler SM, Dyer KA, Goldman MA (1992) Mammalian X chromosome inactivation. Mol Genet Med 2:121–160PubMedCrossRefGoogle Scholar
  57. Genesio R, Melis D, Gatto S et al (2011) Variegated silencing through epigenetic modifications of a large Xq region in a case of balanced X;2 translocation with Incontinentia Pigmenti-like phenotype. Epigenetics 6:1242–1247. doi: 10.4161/epi.6.10.17698 PubMedCrossRefGoogle Scholar
  58. Giacalone JP, Francke U (1992) Common sequence motifs at the rearrangement sites of a constitutional X/autosome translocation and associated deletion. Am J Hum Genet 50:725–741PubMedPubMedCentralGoogle Scholar
  59. Giliberto F, Radic CP, Luce L et al (2014) Symptomatic female carriers of Duchenne muscular dystrophy (DMD): genetic and clinical characterization. J Neurol Sci 336(1–2):36–41. doi: 10.1016/j.jns.2013.09.036 PubMedCrossRefGoogle Scholar
  60. Gontan C, Achame EM, Demmers J et al (2012) RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation. Nature 485:386–390. doi: 10.1038/nature11070 PubMedCrossRefGoogle Scholar
  61. Gorski JL (1991) 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 40:332–337. doi: 10.1002/ajmg.1320400317 PubMedCrossRefGoogle Scholar
  62. Grain L, Cortina-Borja M, Forfar C et al (2001) Cardiac abnormalities and skeletal muscle weakness in carriers of Duchenne and Becker muscular dystrophies and controls. Neuromuscul Disord 11:186–191PubMedCrossRefGoogle Scholar
  63. Greenstein RM, Reardon MP, Chan TS et al (1980) An (X;11) translocation in a girl with Duchenne muscular dystrophy. Repository identification No. GM1695. Cytogenet Cell Genet 27:268PubMedCrossRefGoogle Scholar
  64. Grzeschik K-H, Kim MA, Johannsmann R (1975) Late replicating bands of human chromosomes demonstrated by fluorochrome and Giemsa staining. Hum Genet 29:41–59. doi: 10.1007/BF00273350 CrossRefGoogle Scholar
  65. Gupta N, Goel H, Phadke SR (2006) Unbalanced X; autosome translocation. Indian J Pediatr 73:840–842PubMedCrossRefGoogle Scholar
  66. Hall LL, Clemson CM, Byron M et al (2002) Unbalanced X;autosome translocations provide evidence for sequence specificity in the association of XIST RNA with chromatin. Hum Mol Genet 11:3157–3165. doi: 10.1093/hmg/11.25.3157 PubMedCrossRefGoogle Scholar
  67. Hoffman EP, Pegoraro E, Scacheri P et al (1996) Genetic counseling of isolated carriers of Duchenne muscular dystrophy. Am J Med Genet 63:573–580. doi: 10.1002/(SICI)1096-8628(19960628)63:4<573:AID-AJMG11>3.0.CO;2-F PubMedCrossRefGoogle Scholar
  68. Holden JJ, Smith A, MacLeod PM et al (1986) Xp21/autosome translocations. Case report and risk for Duchenne muscular dystrophy. Clin Genet 29:516–522PubMedCrossRefGoogle Scholar
  69. Hoogerwaard EM, van der Wouw PA, Wilde AA et al (1999) Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy. Neuromuscul Disord 9:347–351PubMedCrossRefGoogle Scholar
  70. Jacobs PA, Hunt PA, Mayer M, Bart RD (1981) Duchenne muscular dystrophy (DMD) in a female with an X/autosome translocation: further evidence that the DMD locus is at Xp21. Am J Hum Genet 33:513–518PubMedPubMedCentralGoogle Scholar
  71. Jonàs Juan-Mateu MJR (2012) Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy. Orphanet J Rare Dis 7:82. doi: 10.1186/1750-1172-7-82 PubMedPubMedCentralCrossRefGoogle Scholar
  72. Kalz-Füller B (1999) Characterisation, phenotypic manifestations and X-inactivation pattern in 14 patients with X-autosome translocations. Clin Genet 55:363–367CrossRefGoogle Scholar
  73. Karpati G, Zubrzycka-Gaarn EE, Carpenter S et al (1990) Age-related conversion of dystrophin-negative to -positive fiber segments of skeletal but not cardiac muscle fibers in heterozygote mdx mice. J Neuropathol Exp Neurol 49:96–105PubMedCrossRefGoogle Scholar
  74. Kimura S, Mitsuda T, Misugi N et al (1986) Clinical features in a girl with Duchenne muscular dystrophy with an X-autosome translocation; (X;4)(p21;q26). Brain Dev 8:619–623PubMedCrossRefGoogle Scholar
  75. Kind J, van Steensel B (2010) Genome-nuclear lamina interactions and gene regulation. Curr Opin Cell Biol 22:320–325. doi: 10.1016/j.ceb.2010.04.002 PubMedCrossRefGoogle Scholar
  76. Knudsen GPS, Pedersen J, Klingenberg O, Lygren I, Ørstavik KH (2007) Increased skewing of X chromosome inactivation with age in both blood and buccal cells. Cytogenet Genome Res 116:24–28PubMedCrossRefGoogle Scholar
  77. Kristiansen M, Knudsen GPS, Bathum L, Naumova AK, Sørensen TIA, Brix TH et al (2005) Twin study of genetic and aging effects on X chromosome inactivation. Eur J Hum Genet 13:599–606PubMedCrossRefGoogle Scholar
  78. Kyriakides T, Pegoraro E, Hoffman EP et al (2011) SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy: predicting the severity of Duchenne muscular dystrophy: implications for treatment. Neurology. 77:1858. doi: 10.1212/WNL.0b013e318239b9ae (author reply 1858–9) PubMedCrossRefGoogle Scholar
  79. Lanasa MC, Hogge WA, Kubik CJ, Ness RB, Harger J, Nagel T et al (2001) A novel X chromosome-linked genetic cause of recurrent spontaneous abortion. Am J Obstet Gynecol 185:563–568PubMedCrossRefGoogle Scholar
  80. Laurent C, Biemont MC, Dutrillaux B (1975) Four new cases of X-autosome translocation in man (author’s transl). Humangenetik 26:35–46PubMedGoogle Scholar
  81. Lee JT (2005) Regulation of X-chromosome counting by Tsix and Xite sequences. Science 309:768–771. doi: 10.1126/science.1113673 PubMedCrossRefGoogle Scholar
  82. Lindenbaum RH, Clarke G, Patel C et al (1979) Muscular dystrophy in an X; 1 translocation female suggests that Duchenne locus is on X chromosome short arm. J Med Genet 16:389–392PubMedPubMedCentralCrossRefGoogle Scholar
  83. Lupski JR, Garcia CA, Zoghbi HY et al (1991) 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 40:354–364. doi: 10.1002/ajmg.1320400323 PubMedCrossRefGoogle Scholar
  84. Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373PubMedCrossRefGoogle Scholar
  85. MacLeod PM, Holden J, Masotti R (1983) Duchenne muscular dystrophy in a female with an X-autosome translocation. Int Congr Genetics, New DelhiGoogle Scholar
  86. Masui O, Bonnet I, Le Baccon P et al (2011) Live-cell chromosome dynamics and outcome of X chromosome pairing events during ES cell differentiation. Cell 145:447–458. doi: 10.1016/j.cell.2011.03.032 PubMedPubMedCentralCrossRefGoogle Scholar
  87. Matsumura K, Ohlendieck K, Ionasescu VV et al (1993) The role of the dystrophin–glycoprotein complex in the molecular pathogenesis of muscular dystrophies. Neuromuscul Disord 3:533–535PubMedCrossRefGoogle Scholar
  88. Mattei MG, Mattei JF, Vidal I, Girauld F (1981) Structural anomalies of the X chromosome and inactivation center. Hum Genet 56:401–408PubMedCrossRefGoogle Scholar
  89. Mattei MG, Mattei JF, Ayme S, Giraud F (1982) X-autosome translocations: cytogenetic characteristics and their consequences. Hum Genet 61:295–309PubMedCrossRefGoogle Scholar
  90. Matthews PM, Benjamin D, Van Bakel I et al (1995) Muscle X-inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers. Neuromuscul Disord 5:209–220. doi: 10.1016/0960-8966(94)00057-G PubMedCrossRefGoogle Scholar
  91. Meitinger T, Boyd Y, Anand R, Craig IW (1988) Mapping of Xp21 translocation breakpoints in and around the DMD gene by pulsed field gel electrophoresis. Genomics 3:315–322PubMedCrossRefGoogle Scholar
  92. Migeon BR (2006) The role of X inactivation and cellular mosaicism in women’s health and sex-specific diseases. JAMA 295:1428–1433PubMedCrossRefGoogle Scholar
  93. Migeon BR (2007) Why females are mosaics, X-chromosome inactivation, and sex differences in disease. Gend Med 4:97–105PubMedCrossRefGoogle Scholar
  94. Moser H, Emery AE (1974) The manifesting carrier in Duchenne muscular dystrophy. Clin Genet 5:271–284PubMedCrossRefGoogle Scholar
  95. Moss FP, Leblond CP (1971) Satellite cells as the source of nuclei in muscles of growing rats. Anat Rec 170:421–435. doi: 10.1002/ar.1091700405 PubMedCrossRefGoogle Scholar
  96. Narazaki O, Hanai T, Ueki Y, Mitsudome A (1985) Duchenne muscular dystrophy in a female with an X-autosome translocation. Rinsho Shinkeigaku 25:432–436PubMedGoogle Scholar
  97. Naumova AK, Olien L, Bird LM, Smith M, Verner AE, Leppert M, Morgan K, Sapienza C (1998) Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human. Eur J Hum Genet 6:552–562PubMedCrossRefGoogle Scholar
  98. Nevin NC, Hughes AE, Calwell M, Lim JH (1986) Duchenne muscular dystrophy in a female with a translocation involving Xp21. J Med Genet 23:171–173PubMedPubMedCentralCrossRefGoogle Scholar
  99. Nigro G, Di Somma S, Comi LI et al (1995) Structural basis of cardiomyopathy in Duchenne/Becker carriers. Endomyocardial biopsy evaluation. Ann NY Acad Sci 752:108–110PubMedCrossRefGoogle Scholar
  100. Nigro G, Comi L, Politano L, Nigro Ge (2004) Cardiomyopathies associated with muscular dystrophies. In: Engel AG, Franzini-Armstrong C (eds) Myology, 3rd edn. McGraw-Hill, New York, pp 1239–1256Google Scholar
  101. Nora EP, Lajoie BR, Schulz EG et al (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485:381–385. doi: 10.1038/nature11049 PubMedPubMedCentralCrossRefGoogle Scholar
  102. Nowak KJ, Davies KE (2004) Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO Rep 5:872–876. doi: 10.1038/sj.embor.7400221 PubMedPubMedCentralCrossRefGoogle Scholar
  103. Obersztyn E, Szczaluba K, Smyk M et al (2008) Duchenne muscular dystrophy (DMD) in a girl with balanced translocation (X;3)(p21.1;p13) and psychomotor delay. Eur J Paediatr Neurol 12(Supplement 1):S54–S55. doi: 10.1016/S1090-3798(08)70182-X CrossRefGoogle Scholar
  104. Okamoto I, Otte AP, Allis CD et al (2004) Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303:644–649. doi: 10.1126/science.1092727 PubMedCrossRefGoogle Scholar
  105. Okumura K, Fujimori Y, Takagi A et al (2008) Skewed X chromosome inactivation in fraternal female twins results in moderately severe and mild haemophilia B. Haemophilia 14:1088–1093. doi: 10.1111/j.1365-2516.2008.01786.x PubMedCrossRefGoogle Scholar
  106. Orstavik KH (2009) X chromosome inactivation in clinical practice. Hum Genet 126:363–373. doi: 10.1007/s00439-009-0670-5 PubMedCrossRefGoogle Scholar
  107. Orstavik KH, Orstavik RE, Halse J, Knudtzon J (1996) X chromosome inactivation pattern in female carriers of X linked hypophosphataemic rickets. J Med Genet 33:700–703PubMedPubMedCentralCrossRefGoogle Scholar
  108. Orstavik KH, Orstavik RE, Schwartz M (1999) 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 36:865–866PubMedPubMedCentralGoogle Scholar
  109. Palmer CG, Hubbard TW, Henry GW, Weaver DD (1980) Failure of X inactivation in the autosomal segment of an X/A translocation. Am J Hum Genet 32:179–187PubMedPubMedCentralGoogle Scholar
  110. Palmucci L, Doriguzzi C, Mongini T et al (1999) Unusual clinical expression of dystrophinopathy in a female, mimicking a congenital myopathy. Eur Neurol 42:221–224PubMedCrossRefGoogle Scholar
  111. Pegoraro E, Schimke RN, Arahata K et al (1994) Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. Am J Hum Genet 54:989–1003PubMedPubMedCentralGoogle Scholar
  112. Pegoraro E, Schimke RN, Garcia C et al (1995) Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei. Neurology 45:677–690PubMedCrossRefGoogle Scholar
  113. Perez Vidal M, SarretGrau E, PratsViñas J et al (1983) Distrofia muscular tipo Duchenne.en una hembra con una translocacion equilibrada X/6. Revista de Neurologia 11:155–158Google Scholar
  114. Pikó H, Vancsó V, Nagy B et al (2009) Dystrophin gene analysis in Hungarian Duchenne/Becker muscular dystrophy families—detection of carrier status in symptomatic and asymptomatic female relatives. Neuromuscul Disord 19:108–112. doi: 10.1016/j.nmd.2008.10.011 PubMedCrossRefGoogle Scholar
  115. Plath K, Fang J, Mlynarczyk-Evans SK et al (2003) Role of histone H3 lysine 27 methylation in X inactivation. Science 300:131–135. doi: 10.1126/science.1084274 PubMedCrossRefGoogle Scholar
  116. Plenge RM, Hendrich BD, Schwartz C, Arena JF, Naumova A, Sapienza C et al (1997) A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat Genet 17:353–356PubMedCrossRefGoogle Scholar
  117. Politano L, Comi L, Nigro G (1986) Dystrophic cardiomyopathy in Duchenne definite carriers (electrocardiographic and echocardiographic findings). Cardiomyology 5:139–151Google Scholar
  118. Politano L, Nigro V, Nigro G et al (1996) Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies. JAMA 275:1335–1338PubMedCrossRefGoogle Scholar
  119. Quan F, Janas J, Toth-Fejel S, Johnson DB, Wolford JK, Popovich BW (1997) Uniparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy. Am J Hum Genet 60:160–165PubMedPubMedCentralGoogle Scholar
  120. Reinius B, Shi C, Hengshuo L et al (2010) Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse. BMC Genom 11:614. doi: 10.1186/1471-2164-11-614 CrossRefGoogle Scholar
  121. Renault NK, Dyack S, Dobson MJ, Costa T, Lam WL, Greer WL (2007) Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females. Eur J Hum Genet 15:628–637PubMedCrossRefGoogle Scholar
  122. Ribeiro MC, Melaragno MI, Schmidt B et al (1986) Duchenne muscular dystrophy in a girl with an (X;15) translocation. Am J Med Genet 25:231–236. doi: 10.1002/ajmg.1320250205 PubMedCrossRefGoogle Scholar
  123. Robinson DO, Boyd Y, Cockburn D et al (1990) The parental origin of de novo X-autosome translocations in females with Duchenne muscular dystrophy revealed by M27 beta methylation analysis. Genet Res 56:135–140PubMedCrossRefGoogle Scholar
  124. Romero NB, De Lonlay P, Llense S et al (2001) Pseudo-metabolic presentation in a Duchenne muscular dystrophy symptomatic carrier with “de novo” duplication of dystrophin gene. Neuromuscul Disord 11:494–498PubMedCrossRefGoogle Scholar
  125. Ross MT, Grafham DV, Coffey AJ et al (2005) The DNA sequence of the human X chromosome. Nature 434:325–337. doi: 10.1038/nature03440 PubMedPubMedCentralCrossRefGoogle Scholar
  126. Russell LB (1963) Mammalian X-chromosome action: inactivation limited in spread and region of origin. Science 140:976–978PubMedCrossRefGoogle Scholar
  127. Saito F, Tonomura A, Kimura S et al (1985) High-resolution banding study of an X/4 translocation in a female with Duchenne muscular dystrophy. Hum Genet 71:370–371PubMedCrossRefGoogle Scholar
  128. Sandra Mercier AT (2013) Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age. Eur J Hum Genet EJHG 21:892. doi: 10.1038/ejhg.2013.74 CrossRefGoogle Scholar
  129. Satoh M, Ogikubo S, Yoshizawa-Ogasawara A (2008) Correlation between clinical phenotypes and X-inactivation patterns in six female carriers with heterozygote vasopressin type 2 receptor gene mutations. Endocr J 55:277–284PubMedCrossRefGoogle Scholar
  130. Satre V, Monnier N, Devillard F et al (2004) Prenatal diagnosis of DMD in a female foetus affected by Turner syndrome. Prenat Diagn 24:913–917. doi: 10.1002/pd.1031 PubMedCrossRefGoogle Scholar
  131. Schmidt M, Du Sart D (1992) 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 42:161–169. doi: 10.1002/ajmg.1320420205 PubMedCrossRefGoogle Scholar
  132. Seemann N, Selby K, McAdam L et al (2011) Symptomatic dystrophinopathies in female children. Neuromuscul Disord 21:172–177. doi: 10.1016/j.nmd.2010.11.001 PubMedCrossRefGoogle Scholar
  133. Segalés J, Perdiguero E, Muñoz-Cánoves P (2014) Epigenetic control of adult skeletal muscle stem cell functions. FEBS J. doi: 10.1111/febs.13065 PubMedGoogle Scholar
  134. Sharp AJ, Spotswood HT, Robinson DO et al (2002) Molecular and cytogenetic analysis of the spreading of X inactivation in X;autosome translocations. Hum Mol Genet 11:3145–3156PubMedCrossRefGoogle Scholar
  135. Soltanzadeh P, Friez MJ, Dunn D et al (2010) Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord 20:499–504. doi: 10.1016/j.nmd.2010.05.010 PubMedPubMedCentralCrossRefGoogle Scholar
  136. Splinter E, de Wit E, Nora EP et al (2011) The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA. Genes Dev 25:1371–1383. doi: 10.1101/gad.633311 PubMedPubMedCentralCrossRefGoogle Scholar
  137. Stankiewicz P, Kuechler A, Eller CD et al (2006) Minimal phenotype in a girl with trisomy 15q due to t(X;15)(q22.3;q11.2) translocation. Am J Med Genet A 140:442–452. doi: 10.1002/ajmg.a.31096 PubMedCrossRefGoogle Scholar
  138. Sumita DR, Vainzof M, Campiotto S et al (1998) Absence of correlation between skewed X inactivation in blood and serum creatine-kinase levels in Duchenne/Becker female carriers. Am J Med Genet 80:356–361PubMedCrossRefGoogle Scholar
  139. Tanner SM, Orstavik KH, Kristiansen M, Lev D, Lerman-Sagie T, Sadeh M et al (1999) Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother. Hum Genet 104:249–253PubMedCrossRefGoogle Scholar
  140. Tihy F, Vogt N, Recan D et al (1994) Skewed inactivation of an X chromosome deleted at the dystrophin gene in an asymptomatic mother and her affected daughter. Hum Genet 93:563–567PubMedCrossRefGoogle Scholar
  141. Tomkins DJ, McDonald HL, Farrell SA, Brown CJ (2002) 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. Eur J Hum Genet 10:44–51PubMedCrossRefGoogle Scholar
  142. Trippe H, Wieczorek S, Kötting J et al (2014) Xp21/A translocation: a rarely considered genetic cause for manifesting carriers of duchenne muscular dystrophy. Neuropediatrics 45:333–335. doi: 10.1055/s-0034-1383824 PubMedCrossRefGoogle Scholar
  143. van Bakel I, Holt S, Craig I, Boyd Y (1995) Sequence analysis of the breakpoint regions of an X;5 translocation in a female with Duchenne muscular dystrophy. Am J Hum Genet 57:329–336PubMedPubMedCentralGoogle Scholar
  144. Verellen-Dumoulin C, Freund M, Meyer RD et al (1984) Expression of an X-linked muscular dystrophy in a female due to translocation involving Xp21 and non-random inactivation of the normal X chromosome. Hum Genet 67:115–119. doi: 10.1007/BF00270570 PubMedCrossRefGoogle Scholar
  145. Vickers MA, McLeod E, Spector TD, Wilson I (2001) Assessment of mechanism of acquired skewed X inactivation by analysis of twins. Blood 97:1274–1281PubMedCrossRefGoogle Scholar
  146. Viggiano E, Picillo E, Cirillo A, Politano L (2013a) Comparison of X-chromosome inactivation in Duchenne muscle/myocardium-manifesting carriers, non-manifesting carriers and related daughters. Clin Genet 84:265–270. doi: 10.1111/cge.12048 PubMedCrossRefGoogle Scholar
  147. Viggiano E, Picillo E, Politano L (2013b) DMD phenotype in girls with a de novo balanced X;3 autosome translocation: a case report. J Genet Syndr Gene Ther 4:132. doi: 10.4172/2157-7412.1000132 Google Scholar
  148. Wang Z, Willard HF, Mukherjee S, Furey TS (2006a) Evidence of influence of genomic DNA sequence on human X chromosome inactivation. PLoS Comput Biol 2:e113. doi: 10.1371/journal.pcbi.0020113 PubMedPubMedCentralCrossRefGoogle Scholar
  149. Wang Z, Willard HF, Mukherjee S, Furey TS (2006b) Evidence of influence of genomic DNA sequence on human X chromosome inactivation. PLoS Comput Biol 2:e113. doi: 10.1371/journal.pcbi.0020113 PubMedPubMedCentralCrossRefGoogle Scholar
  150. Waters JJ, Campbell PL, Crocker AJ, Campbell CM (2001) Phenotypic effects of balanced X-autosome translocations in females: a retrospective survey of 104 cases reported from UK laboratories. Hum Genet 108:318–327PubMedCrossRefGoogle Scholar
  151. Watkins SC, Hoffman EP, Slayter HS, Kunkel LM (1989) Dystrophin distribution in heterozygote MDX mice. Muscle Nerve 12:861–868. doi: 10.1002/mus.880121013 PubMedCrossRefGoogle Scholar
  152. Weller B, Karpati G, Lehnert S et al (1991) Inhibition of myosatellite cell proliferation by gamma irradiation does not prevent the age-related increase of the number of dystrophin-positive fibers in soleus muscles of mdx female heterozygote mice. Am J Pathol 138:1497–1502PubMedPubMedCentralGoogle Scholar
  153. Wenger SL, Steele MW, Hoffman EP et al (1992) X inactivation and dystrophin studies in a t(X;12) female: evidence for biochemical normalization in Duchenne muscular dystrophy carriers. Am J Med Genet 43:1012–1015. doi: 10.1002/ajmg.1320430619 PubMedCrossRefGoogle Scholar
  154. Willard HF, Latt SA (1976) Analysis of deoxyribonucleic acid replication in human X chromosomes by fluorescence microscopy. Am J Hum Genet 28:213–227PubMedPubMedCentralGoogle Scholar
  155. Yoon J, Kim SH, Ki CS et al (2011) Carrier woman of Duchenne muscular dystrophy mimicking inflammatory myositis. J Korean Med Sci 26:587–591. doi: 10.3346/jkms.2011.26.4.587 PubMedPubMedCentralCrossRefGoogle Scholar
  156. Yoshioka M, Yorifuji T, Mituyoshi I (1998) Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy. Clin Genet 53:102–107PubMedCrossRefGoogle Scholar
  157. Zatz M, Vianna-Morgante AM, Campos P, Diament AJ (1981) Translocation (X;6) in a female with Duchenne muscular dystrophy: implications for the localisation of the DMD locus. J Med Genet 18:442–447PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Emanuela Viggiano
    • 1
  • Manuela Ergoli
    • 1
  • Esther Picillo
    • 1
  • Luisa Politano
    • 1
  1. 1.Cardiomyology and Medical Genetics, Department of Experimental Medicine, I PoliclinicoSecond University of NaplesNaplesItaly

Personalised recommendations