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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2012

Open Access 01-12-2012 | Research

Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

Authors: Jonàs Juan-Mateu, Maria José Rodríguez, Andrés Nascimento, Cecilia Jiménez-Mallebrera, Lidia González-Quereda, Eloy Rivas, Carmen Paradas, Marcos Madruga, Pedro Sánchez-Ayaso, Cristina Jou, Laura González-Mera, Francina Munell, Manuel Roig-Quilis, Maria Rabasa, Aurelio Hernández-Lain, Jorge Díaz-Manera, Eduard Gallardo, Jordi Pascual, Edgard Verdura, Jaume Colomer, Montserrat Baiget, Montse Olivé, Pia Gallano

Published in: Orphanet Journal of Rare Diseases | Issue 1/2012

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Abstract

Background

Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy.

Methods

We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females.

Results

Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found.

Conclusions

Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.
Appendix
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Literature
1.
Muntoni F, Torelli S, Ferlini A: Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol. 2003 Dec, 2 (12): 731-740. 10.1016/S1474-4422(03)00585-4.CrossRefPubMed
2.
Cotton S, Voudouris NJ, Greenwood KM: Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients. Dev Med Child Neurol. 2001 Jul, 43 (7): 497-501. 10.1017/S0012162201000913.CrossRefPubMed
3.
Aartsma-Rus A, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT: Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve. 2006 Aug, 34 (2): 135-144. 10.1002/mus.20586.CrossRefPubMed
4.
Tuffery-Giraud S, Beroud C, Leturcq F, Yaou RB, Hamroun D, Michel-Calemard L, Moizard MP, Bernard R, Cossee M, Boisseau P, Blayau M, Creveaux I, Guiochon-Mantel A, de Martinville B, Philippe C, Monnier N, Bieth E, Khau Van Kien P, Desmet FO, Humbertclaude V, Kaplan JC, Chelly J, Claustres M: Hum Mutat. 2009, 30 (6): 934-945. 10.1002/humu.20976.CrossRefPubMed
5.
Monaco AP, Bertelson CJ, Liechti-Gallati S, Moser H, Kunkel LM: An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics. 1988 Jan, 2 (1): 90-95. 10.1016/0888-7543(88)90113-9.CrossRefPubMed
6.
Bushby KM, Goodship JA, Nicholson LV, Johnson MA, Haggerty ID, Gardner-Medwin D: Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy. Neuromuscul Disord. 1993 Jan, 3 (1): 57-64. 10.1016/0960-8966(93)90042-I.CrossRefPubMed
7.
Norman A, Harper P: A survey of manifesting carriers of Duchenne and Becker muscular dystrophy in Wales. Clin Genet. 1989 Jul, 36 (1): 31-37.CrossRefPubMed
8.
Seemann N, Selby K, McAdam L, Biggar D, Kolski H, Goobie S, Yoon G, Campbell C, Canadian Pediatric Neuromuscular Group: Symptomatic dystrophinopathies in female children. Neuromuscul Disord. 2011 Mar, 21 (3): 172-177. 10.1016/j.nmd.2010.11.001.CrossRefPubMed
9.
Rajakulendran S, Kuntzer T, Dunand M, Yau SC, Ashton EJ, Storey H, McCauley J, Abbs S, Thonney F, Leturcq F, Lobrinus JA, Yousry T, Farmer S, Holton JL, Hanna MG: Marked hemiatrophy in carriers of Duchenne muscular dystrophy. Arch Neurol. 2010 Apr, 67 (4): 497-500. 10.1001/archneurol.2010.58.CrossRefPubMed
10.
Soltanzadeh P, Friez MJ, Dunn D, von Niederhausern A, Gurvich OL, Swoboda KJ, Sampson JB, Pestronk A, Connolly AM, Florence JM, Finkel RS, Bonnemann CG, Medne L, Mendell JR, Mathews KD, Wong BL, Sussman MD, Zonana J, Kovak K, Gospe SM Jr, Gappmaier E, Taylor LE, Howard MT, Weiss RB, Flanigan KM: Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord. 2010 Aug, 20 (8): 499-504. 10.1016/j.nmd.2010.05.010.PubMedCentralCrossRefPubMed
11.
Yoshioka M: Clinically manifesting carriers in Duchenne muscular dystrophy. Clin Genet. 1981 Jul, 20 (1): 6-12.CrossRefPubMed
12.
Hoogerwaard EM, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF, Leschot NJ, Van Essen AJ, Brunner HG, van der Wouw PA, Wilde AA, de Visser M: Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study. Lancet. 1999 Jun 19, 353 (9170): 2116-2119. 10.1016/S0140-6736(98)10028-4.CrossRefPubMed
13.
Boyd Y, Buckle V, Holt S, Munro E, Hunter D, Craig I: Muscular dystrophy in girls with X;autosome translocations. J Med Genet. 1986 Dec, 23 (6): 484-490. 10.1136/jmg.23.6.484.PubMedCentralCrossRefPubMed
14.
Fujii K, Minami N, Hayashi Y, Nishino I, Nonaka I, Tanabe Y, Takanashi J, Kohno Y: Homozygous female Becker muscular dystrophy. Am J Med Genet A. 2009 May, 149A (5): 1052-1055. 10.1002/ajmg.a.32808.CrossRefPubMed
15.
Chelly J, Marlhens F, Le Marec B, Jeanpierre M, Lambert M, Hamard G, Dutrillaux B, Kaplan JC: De novo DNA microdeletion in a girl with Turner syndrome and Duchenne muscular dystrophy. Hum Genet. 1986 Oct, 74 (2): 193-196. 10.1007/BF00282093.CrossRefPubMed
16.
Satre V, Monnier N, Devillard F, Amblard F, Lunardi J: Prenatal diagnosis of DMD in a female foetus affected by Turner syndrome. Prenat Diagn. 2004 Nov, 24 (11): 913-917. 10.1002/pd.1031.CrossRefPubMed
17.
Baiget M, Tizzano E, Volpini V, del Rio E, Perez-Vidal T, Gallano P: DMD carrier detection in a female with mosaic Turner's syndrome. J Med Genet. 1991 Mar, 28 (3): 209-210. 10.1136/jmg.28.3.209.PubMedCentralCrossRefPubMed
18.
Quan F, Janas J, Toth-Fejel S, Johnson DB, Wolford JK, Popovich BW: Uniparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy. Am J Hum Genet. 1997 Jan, 60 (1): 160-165.PubMedCentralPubMed
19.
Katayama Y, Tran VK, Hoan NT, Zhang Z, Goji K, Yagi M, Takeshima Y, Saiki K, Nhan NT, Matsuo M: Co-occurrence of mutations in both dystrophin- and androgen-receptor genes is a novel cause of female Duchenne muscular dystrophy. Hum Genet. 2006 Jun, 119 (5): 516-519. 10.1007/s00439-006-0159-4.CrossRefPubMed
20.
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 Aug, 96 (2): 167-176. 10.1007/BF00207374.CrossRefPubMed
21.
Yoshioka M, Yorifuji T, Mituyoshi I: Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy. Clin Genet. 1998 Feb, 53 (2): 102-107.CrossRefPubMed
22.
Pegoraro E, Schimke RN, Arahata K, Hayashi Y, Stern H, Marks H, Glasberg MR, Carroll JE, Taber JW, Wessel HB: Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. Am J Hum Genet. 1994 Jun, 54 (6): 989-1003.PubMedCentralPubMed
23.
Matthews PM, Benjamin D, Van Bakel I, Squier MV, Nicholson LV, Sewry C, Barnes PR, Hopkin J, Brown R, Hilton-Jones D: Muscle X-inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers. Neuromuscul Disord. 1995 May, 5 (3): 209-220. 10.1016/0960-8966(94)00057-G.CrossRefPubMed
24.
Sumita DR, Vainzof M, Campiotto S, Cerqueira AM, Canovas M, Otto PA, Passos-Bueno MR, Zatz M: Absence of correlation between skewed X inactivation in blood and serum creatine-kinase levels in Duchenne/Becker female carriers. Am J Med Genet. 1998 Dec 4, 80 (4): 356-361. 10.1002/(SICI)1096-8628(19981204)80:4<356::AID-AJMG10>3.0.CO;2-O.CrossRefPubMed
25.
Juan-Mateu J, Paradas C, Olive M, Verdura E, Rivas E, Gonzalez-Quereda L, Rodriguez MJ, Baiget M, Gallano P: Isolated cardiomyopathy caused by a DMD nonsense mutation in somatic mosaicism: genetic normalization in skeletal muscle. Clin Genet. 2011
26.
Flanigan KM, von Niederhausern A, Dunn DM, Alder J, Mendell JR, Weiss RB: Rapid direct sequence analysis of the dystrophin gene. Am J Hum Genet. 2003 Apr, 72 (4): 931-939. 10.1086/374176.PubMedCentralCrossRefPubMed
27.
Deburgrave N, Daoud F, Llense S, Barbot JC, Recan D, Peccate C, Burghes AH, Beroud C, Garcia L, Kaplan JC, Chelly J, Leturcq F: Protein- and mRNA-based phenotype-genotype correlations in DMD/BMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene. Hum Mutat. 2007 Feb, 28 (2): 183-195. 10.1002/humu.20422.CrossRefPubMed
28.
Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW: 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 Dec, 51 (6): 1229-1239.PubMedCentralPubMed
29.
Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J, Willard HF: X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet. 2006 Sep, 79 (3): 493-499. 10.1086/507565.PubMedCentralCrossRefPubMed
30.
Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N: Requirement for Xist in X chromosome inactivation. Nature. 1996 Jan 11, 379 (6561): 131-137. 10.1038/379131a0.CrossRefPubMed
31.
Plenge RM, Hendrich BD, Schwartz C, Arena JF, Naumova A, Sapienza C, Winter RM, Willard HF: A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat Genet. 1997 Nov, 17 (3): 353-356. 10.1038/ng1197-353.CrossRefPubMed
32.
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. Eur J Hum Genet. 2002 Jan, 10 (1): 44-51. 10.1038/sj.ejhg.5200757.CrossRefPubMed
33.
Hoffman EP, Arahata K, Minetti C, Bonilla E, Rowland LP: Dystrophinopathy in isolated cases of myopathy in females. Neurology. 1992 May, 42 (5): 967-975. 10.1212/WNL.42.5.967.CrossRefPubMed
34.
Hoogerwaard EM, Ginjaar IB, Bakker E, de Visser M: Dystrophin analysis in carriers of Duchenne and Becker muscular dystrophy. Neurology. 2005 Dec 27, 65 (12): 1984-1986. 10.1212/01.wnl.0000188909.89849.59.CrossRefPubMed
35.
van Essen AJ, Mulder IM, van der Vlies P, van der Hout AH, Buys CH, Hofstra RM, den Dunnen JT: Detection of point mutation in dystrophin gene reveals somatic and germline mosaicism in the mother of a patient with Duchenne muscular dystrophy. Am J Med Genet A. 2003 Apr 30, 118A (3): 296-298. 10.1002/ajmg.a.10056.CrossRefPubMed
36.
Taylor PJ, Betts GA, Maroulis S, Gilissen C, Pedersen RL, Mowat DR, Johnston HM, Buckley MF: Dystrophin gene mutation location and the risk of cognitive impairment in Duchenne muscular dystrophy. PLoS One. 2010 Jan 20, 5 (1): e8803-10.1371/journal.pone.0008803.PubMedCentralCrossRefPubMed
37.
Pegoraro E, Schimke RN, Garcia C, Stern H, Cadaldini M, Angelini C, Barbosa E, Carroll J, Marks WA, Neville HE, Marks H, Appleton S, Toriello H, Wessel HB, Donnelly J, Bernes SM, Taber JW, Weiss L, Hoffman EP: Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei. Neurology. 1995 Apr, 45 (4): 677-690. 10.1212/WNL.45.4.677.CrossRefPubMed
38.
Kesari A, Neel R, Wagoner L, Harmon B, Spurney C, Hoffman EP: Somatic mosaicism for Duchenne dystrophy: evidence for genetic normalization mitigating muscle symptoms. Am J Med Genet A. 2009 Jul, 149A (7): 1499-1503. 10.1002/ajmg.a.32891.PubMedCentralCrossRefPubMed
39.
Brown CJ, Robinson WP: The causes and consequences of random and non-random X chromosome inactivation in humans. Clin Genet. 2000 Nov, 58 (5): 353-363.CrossRefPubMed
40.
Pegoraro E, Whitaker J, Mowery-Rushton P, Surti U, Lanasa M, Hoffman EP: Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28. Am J Hum Genet. 1997 Jul, 61 (1): 160-170. 10.1086/513901.PubMedCentralCrossRefPubMed
41.
Cau M, Addis M, Congiu R, Meloni C, Cao A, Santaniello S, Loi M, Emma F, Zuffardi O, Ciccone R, Sole G, Melis MA: A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome. J Hum Genet. 2006, 51 (11): 1030-1036. 10.1007/s10038-006-0049-6.CrossRefPubMed
Metadata
Title
Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
Authors
Jonàs Juan-Mateu
Maria José Rodríguez
Andrés Nascimento
Cecilia Jiménez-Mallebrera
Lidia González-Quereda
Eloy Rivas
Carmen Paradas
Marcos Madruga
Pedro Sánchez-Ayaso
Cristina Jou
Laura González-Mera
Francina Munell
Manuel Roig-Quilis
Maria Rabasa
Aurelio Hernández-Lain
Jorge Díaz-Manera
Eduard Gallardo
Jordi Pascual
Edgard Verdura
Jaume Colomer
Montserrat Baiget
Montse Olivé
Pia Gallano
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2012
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/1750-1172-7-82

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