Identification of seven novel mutations in the factor VIII gene in 18 unrelated Chinese patients with hemophilia A.
BACKGROUND
Hemophilia A (HA) is an X-linked inherited bleeding disorder caused by decreased activity of factor VIII (FVIII) due to heterogenous mutations in the FVIII coding gene (F8). The type of mutation plays an important role in the FVIII inhibitor formation. To date, several studies on the spectra of F8 defects have been performed in Western populations, but similar studies in Asian races are scarce. Here, we reported the distribution of the F8 gene mutations in 18 unrelated Chinese patients with HA.


METHODS
Intron 22 and intron 1 inversions in the F8 gene were screened in 158 unrelated patients with HA using a long-distance PCR and multiplex PCR method. Direct sequencing of the coding region of the F8 gene was used to identify the mutations responsible for HA in 18 unrelated Chinese HA patients who were negative for intron 22 and intron 1 inversions; sequences were compared with the HAMSTeRS database. A clotting method was used to assay the FVIII activity level and the Bethesda assay was used to detect the FVIII inhibitor.


RESULTS
A total of 18 different HA F8 mutations were identified, seven of which were described for the first time. These novel mutations included five small deletions, one point mutation and one small insertion. One novel mutation (4382-3 AC deletion) was associated with inhibitor development.


CONCLUSIONS
These data extend our insight into the mechanisms by which novel amino acid mutations may lead to HA and how the HA patient genotypes influence the risk of FVIII inhibitor.
Hua
Bao-lai
BL
Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China.
Yan
Zhen-yu
ZY
Liang
Yan
Y
Yan
Mei
M
Fan
Lian-kai
LK
Li
Kui-xing
KX
Xiao
Bai
B
Liu
Jing-zhong
JZ
Zhao
Yong-qiang
YQ
D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D055815:Young Adult
D005169:Factor VIII