The prothrombin 20209 C-->T mutation in Jewish-Moroccan Caucasians: molecular analysis of gain-of-function of 3' end processing.
BACKGROUND
Mutations of the 3' end mRNA-processing signal of the prothrombin (F2) gene have been reported to cause elevated F2 plasma concentrations, thrombosis, and complications of pregnancy. Whereas the common F2 20210*A mutation is almost exclusively found in Caucasians, the F2 20209*T mutation has been reported in Afro-Americans and Afro-Caribbeans only.


METHODS
Using LightCycler technology, three unrelated Jewish-Moroccan patients tested for obstetric complications were found to be carriers of the F2 20209*T allele. A detailed molecular analysis was performed to identify the functional impact of this mutation.


RESULTS
We report three unrelated women of Jewish-Moroccan origin with a F2 20209*T mutation and fetal loss or infertility. The functional analysis revealed that the F2 20209*T mutation stimulates 3' end processing and up-regulates prothrombin protein expression as assessed by a highly sensitive luminescence-based reporter system.


CONCLUSIONS
This is the first report of 20209*T in Caucasians, and functional analysis demonstrates that F2 20209*T falls into a general category of mutations of the F2 gene, which may possibly contribute to thrombophilia and complications of pregnancy by interfering with a tightly balanced architecture of non-canonical F2 3' end formation signals.
Danckwardt
S
S
Departments of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
Hartmann
K
K
Katz
B
B
Hentze
M W
MW
Levy
Y
Y
Eichele
R
R
Deutsch
V
V
Kulozik
A E
AE
Ben-Tal
O
O
D000328:Adult; D000368:Aged; D001483:Base Sequence; D003596:Cytosine / Q000737:chemistry*; D017931:DNA Primers; D005260:Female; D006801:Humans; D007585:Jews; D008297:Male; D009018:Morocco / Q000208:ethnology; D009154:Mutation; D011516:Prothrombin / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013941:Thymine / Q000737:chemistry*; D044465:White People
D017931:DNA Primers; D012333:RNA, Messenger; D003596:Cytosine; D011516:Prothrombin; D013941:Thymine