| Abstract | Our recent studies on the molecular basis of the autosomal recessive disorder congenital afibrinogenemia showed that the most common mutation is a donor splice mutation in FGA intron 4, IVS4 + 1 G-->T, accounting for approximately half of disease alleles. The effect of this mutation on messenger RNA (mRNA) splicing, however, remained unproven. COS-7 cells transfected with a normal plasmid construct produced 100% mRNA molecules with correct splicing, whereas cells transfected with a mutant construct produced multiple aberrant mRNAs, due to utilization of cryptic donor splice sites situated in exon 4 and intron 4. One particular site situated 4 base pairs (bp) downstream of the normal site was used in 85% of transcripts causing afibrinogenemia by a 4-bp insertion-frameshift, leading to premature alpha-chain truncation. Our results confirm the utility of transfecting COS-7 cells to study mRNA splice-site mutations and demonstrate that the common FGA IVS4 variant is a null mutation leading to afibrinogenemia. |
| Authors | C Attanasio, P de Moerloose, S E Antonarakis, M A Morris, M Neerman-Arbez
(Affiliation: Division of Medical Genetics, University Medical School and University Hospital, Geneva, Switzerland.)
|
| Journal | Blood
(Blood)
Vol. 97
Issue 6
Pg. 1879-81
(Mar 15 2001)
ISSN: 0006-4971 United States |
| PMID | 11238133
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- RNA Splice Sites
- Fibrinogen
|
| Topics |
- Afibrinogenemia
(congenital, etiology, genetics)
- Animals
- Base Sequence
- COS Cells
- Exons
(genetics)
- Fibrinogen
(genetics)
- Humans
- Molecular Sequence Data
- Point Mutation
- RNA Splice Sites
(genetics)
- Transfection
|
