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Skewed X chromosome inactivation in fraternal female twins results in moderately severe and mild haemophilia B
Author(s) -
OKUMURA K.,
FUJIMORI Y.,
TAKAGI A.,
MURATE T.,
OZEKI M.,
YAMAMOTO K.,
KATSUMI A.,
MATSUSHITA T.,
NAOE T.,
KOJIMA T.
Publication year - 2008
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/j.1365-2516.2008.01786.x
Subject(s) - medicine , haemophilia , x chromosome , haemophilia a , x inactivation , genetics , chromosome , skewed x inactivation , pediatrics , biology , gene
Summary. Female carriers of haemophilia B are usually asymptomatic; however, the disease resulting from different pathophysiological mechanisms has rarely been documented in females. In this study, we investigated the mechanisms responsible for haemophilia B in fraternal female twins. We sequenced the factor IX gene ( F9 ) of the propositus, her father, a severe haemophilia B patient and the other family members. X chromosome inactivation was assessed by the methylation‐sensitive Hpa II‐PCR assay using X‐linked polymorphisms in human phosphoglycerate kinase 1 gene ( PGK1 ) and glutamate receptor ionotropic AMPA 3 gene ( GRIA3 ). The twins were found to be heterozygotes with a nonsense mutation (p.Arg384X) inherited from their father. The propositus, more severely affected twin, exhibited a significantly higher percentage of inactivation in the maternally derived X chromosome carrying a normal F9 . The other twin also showed a skewed maternal X inactivation, resulting in a patient with mild haemophilia B. Thus, the degree of skewing of maternal X inactivation is closely correlated with the coagulation parameters and the clinical phenotypes of the twins. Furthermore, we identified a crossing‐over in the Xq25–26 region of the maternal X chromosome of the more severely affected twin. This crossing‐over was absent in the other twin, consistent with their fraternal state. Differently skewed X inactivation in the fraternal female twins might cause moderately severe and mild haemophilia B phenotypes, respectively.