Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
Por:
Juan-Mateu, J, Rodriguez, MJ, Nascimento, A, Jimenez-Mallebrera, C, Gonzalez-Quereda, L, Rivas, E, Paradas, C, Madruga, M, Sanchez-Ayaso, P, Jou, C, Gonzalez-Mera, L, Munell, F, Roig-Quilis, M, Rabasa, M, Hernandez-Lain, A, Diaz-Manera, J, Gallardo, E, Pascual, J, Verdura, E, Colomer, J, Baiget, M, Olive, M, Gallano, P
Publicada:
23 oct 2012
Resumen:
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.
Filiaciones:
Juan-Mateu, J:
Hosp Santa Creu & Sant Pau, Serv Genet, Barcelona, Spain
CIBERER, Barcelona, Spain
Univ Barcelona, Barcelona, Spain
Rodriguez, MJ:
Hosp Santa Creu & Sant Pau, Serv Genet, Barcelona, Spain
CIBERER, Barcelona, Spain
Nascimento, A:
Hosp St Joan de Deu, Unitat Patol Neuromuscular, Serv Neurol, Barcelona, Spain
Jimenez-Mallebrera, C:
Hosp St Joan de Deu, Unitat Patol Neuromuscular, Serv Neurol, Barcelona, Spain
Gonzalez-Quereda, L:
Hosp Santa Creu & Sant Pau, Serv Genet, Barcelona, Spain
CIBERER, Barcelona, Spain
Rivas, E:
Hosp Univ Virgen del Rocio, Serv Anat Patol, Seville, Spain
Paradas, C:
Hosp Univ Virgen del Rocio, Unidad Enfermedades Neuromusculares, Serv Neurol, Seville, Spain
Madruga, M:
Hosp Univ Virgen del Rocio, Unidad Neurol Pediat, Seville, Spain
Sanchez-Ayaso, P:
Hosp Gen Univ Albacete, Serv Neurol, Albacete, Spain
Jou, C:
Hosp St Joan de Deu, Serv Anat Patol, Barcelona, Spain
Gonzalez-Mera, L:
Hosp Viladecans, Serv Neurol, Barcelona, Spain
Munell, F:
Hosp Univ Vall dHebron, Inst Recerca, Barcelona, Spain
Roig-Quilis, M:
Hosp Univ Vall dHebron, Inst Recerca, Barcelona, Spain
Hosp Univ Vall dHebron, Secc Neurol Infantil, Hosp Maternoinfantil, Barcelona, Spain
Rabasa, M:
Hosp Univ Fuenlabrada, Fuenlabrada, Spain
Hernandez-Lain, A:
Hosp Univ 12 Octubre, Serv Neuropatol, Madrid, Spain
Diaz-Manera, J:
Univ Autonoma Barcelona, Lab Malalties Neuromusculars, Serv Neurol, Hosp Santa Creu & Sant Pau,Inst Recerca HSCSP, Barcelona, Spain
CIBERNED, Barcelona, Spain
Gallardo, E:
Univ Autonoma Barcelona, Lab Malalties Neuromusculars, Serv Neurol, Hosp Santa Creu & Sant Pau,Inst Recerca HSCSP, Barcelona, Spain
CIBERNED, Barcelona, Spain
Pascual, J:
Hosp del Mar, Serv Neurol, Barcelona, Spain
Verdura, E:
Hosp Santa Creu & Sant Pau, Serv Genet, Barcelona, Spain
CIBERER, Barcelona, Spain
Colomer, J:
Hosp Univ Virgen del Rocio, Serv Anat Patol, Seville, Spain
Baiget, M:
Hosp Santa Creu & Sant Pau, Serv Genet, Barcelona, Spain
CIBERER, Barcelona, Spain
Olive, M:
Bellvitge Hosp, Inst Neuropatol, IDIBELL, Lhospitalet De Llobregat, Catalonia, Spain
CIBERNED, Lhospitalet De Llobregat, Catalonia, Spain
Gallano, P:
Hosp Santa Creu & Sant Pau, Serv Genet, Barcelona, Spain
CIBERER, Barcelona, Spain
Gold, Green Published
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