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

被引：32

作者：

Juan-Mateu, Jonas ^{[1
,2
,3
]}

Jose Rodriguez, Maria ^{[1
,2
]}

Nascimento, Andres ^{[4
]}

Jimenez-Mallebrera, Cecilia ^{[4
]}

Gonzalez-Quereda, Lidia ^{[1
,2
]}

Rivas, Eloy ^{[5
]}

Paradas, Carmen ^{[6
]}

Madruga, Marcos ^{[7
]}

Sanchez-Ayaso, Pedro ^{[8
]}

Jou, Cristina ^{[9
]}

Gonzalez-Mera, Laura ^{[10
]}

Munell, Francina ^{[11
]}

Roig-Quilis, Manuel ^{[11
,12
]}

Rabasa, Maria ^{[13
]}

Hernandez-Lain, Aurelio ^{[14
]}

Diaz-Manera, Jorge ^{[15
,16
]}

Gallardo, Eduard ^{[15
,16
]}

Pascual, Jordi ^{[17
]}

Verdura, Edgard ^{[1
,2
]}

Colomer, Jaume ^{[5
]}

Baiget, Montserrat ^{[1
,2
]}

Olive, Montse ^{[18
,19
]}

Gallano, Pia ^{[1
,2
]}

机构：

[1] Hosp Santa Creu & Sant Pau, Serv Genet, Barcelona, Spain

[2] CIBERER, Barcelona, Spain

[3] Univ Barcelona, Barcelona, Spain

[4] Hosp St Joan de Deu, Unitat Patol Neuromuscular, Serv Neurol, Barcelona, Spain

[5] Hosp Univ Virgen del Rocio, Serv Anat Patol, Seville, Spain

[6] Hosp Univ Virgen del Rocio, Unidad Enfermedades Neuromusculares, Serv Neurol, Seville, Spain

[7] Hosp Univ Virgen del Rocio, Unidad Neurol Pediat, Seville, Spain

[8] Hosp Gen Univ Albacete, Serv Neurol, Albacete, Spain

[9] Hosp St Joan de Deu, Serv Anat Patol, Barcelona, Spain

[10] Hosp Viladecans, Serv Neurol, Barcelona, Spain

[11] Hosp Univ Vall dHebron, Inst Recerca, Barcelona, Spain

[12] Hosp Univ Vall dHebron, Secc Neurol Infantil, Hosp Maternoinfantil, Barcelona, Spain

[13] Hosp Univ Fuenlabrada, Fuenlabrada, Spain

[14] Hosp Univ 12 Octubre, Serv Neuropatol, Madrid, Spain

[15] Univ Autonoma Barcelona, Lab Malalties Neuromusculars, Serv Neurol, Hosp Santa Creu & Sant Pau,Inst Recerca HSCSP, Barcelona, Spain

[16] CIBERNED, Barcelona, Spain

[17] Hosp del Mar, Serv Neurol, Barcelona, Spain

[18] Bellvitge Hosp, Inst Neuropatol, IDIBELL, Lhospitalet De Llobregat, Catalonia, Spain

[19] CIBERNED, Lhospitalet De Llobregat, Catalonia, Spain

来源：

ORPHANET JOURNAL OF RARE DISEASES | 2012年 / 7卷

关键词：

Dystrophin; DMD; Symptomatic carrier; Duchenne muscular dystrophy; Becker muscular dystrophy; X-chromosome inactivation; DUCHENNE MUSCULAR-DYSTROPHY; MANIFESTING CARRIERS; TURNER-SYNDROME; GENE; MUTATIONS; DMD; NORMALIZATION; METHYLATION; EXPRESSION; PHENOTYPES;

D O I：

10.1186/1750-1172-7-82

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：13