Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency.
Methods routinely used for investigating the molecular basis of antithrombin (AT) deficiency do not detect large SERPINC1 rearrangements. Between 2000 and 2008, 86 probands suspected of having AT-inherited type I deficiency were screened for SERPINC1 mutations in our laboratory. Mutations causally linked to the deficiency were identified by sequencing analysis in 63 probands. We present here results of multiplex ligation-dependent probe amplification (MLPA) analysis performed in 22 of the 23 remaining probands, in whom sequencing had revealed no mutation. Large deletions, present at the heterozygous state, were detected in 10 patients: whole gene deletions in 5 and partial deletions removing either exon 6 (n = 2), exons 1-2 (n = 1) or exons 5-7 (n = 2) in 5 others. Exon 6 partial deletions are a 2,769-bp deletion and a 1,892-bp deletion associated with a 10-bp insertion, both having 5' and/or 3' breakpoints located within Alu repeat elements. In addition, we identified the 5' breakpoint of a previously reported deletion of exons 1-2 within an extragenic Alu repeat. Distinct mutational mechanisms explaining these Alu sequence-related deletions are proposed. Overall, in this series, large deletions detected by MLPA explain almost half of otherwise unexplained type I AT-inherited deficiency cases.
Picard
Véronique
V
Service d'Hématologie Biologique, AP-HP, Hôpital Européen Georges Pompidou, 75908 Paris Cedex 15, France. veronique.picard@u-psud.fr
Chen
Jian-Min
JM
Tardy
Brigitte
B
Aillaud
Marie-Françoise
MF
Boiteux-Vergnes
Christine
C
Dreyfus
Marie
M
Emmerich
Joseph
J
Lavenu-Bombled
Cécile
C
Nowak-Göttl
Ulrike
U
Trillot
Nathalie
N
Aiach
Martine
M
Alhenc-Gelas
Martine
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000990:Antithrombin III; D020152:Antithrombin III Deficiency / Q000235:genetics*; D000991:Antithrombins / Q000172:deficiency* / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017384:Sequence Deletion; D055815:Young Adult
D000991:Antithrombins; C542513:SERPINC1 protein, human; D000990:Antithrombin III