Skewed X chromosome inactivation in fraternal female twins results in moderately severe and mild haemophilia B.
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 HpaII-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.
Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
K
K
Okumura
Y
Y
Fujimori
A
A
Takagi
T
T
Murate
M
M
Ozeki
K
K
Yamamoto
A
A
Katsumi
T
T
Matsushita
T
T
Naoe
T
T
Kojima
D015139:Blotting, Southern / Q000379:methods; D004200:Diseases in Twins / Q000235:genetics*; D005164:Factor IX / Q000235:genetics; D005260:Female; D006239:Haplotypes; D002836:Hemophilia B / Q000235:genetics*; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D014429:Twins, Dizygotic / Q000235:genetics*; D049951:X Chromosome Inactivation
D005164:Factor IX