A common origin of the 4143insA ADAMTS13 mutation.
Severely deficient activity of the von Willebrand Factor (VWF) cleaving metalloprotease, ADAMTS13, is associated with thrombotic thrombocytopenic purpura (TTP). The mutation spectrum ofADAMTS13 is rather heterogeneous, and numerous mutations spread across the gene have been described in association with congenital TTP. The 4143insA mutation is unusual with respect to its geographic concentration. Following the initial report from Germany in which the 4143insA mutation was detected in four apparently unrelated families, we have now identified this mutation in a further eleven patients from Norway, Sweden, Poland, Germany, the Czech Republic and Australia. Confirmation that the Australian patient is of German ancestry, together with the Northern and Central European origin of most of the other patients, suggests that the 4143insA mutation has a common genetic background. We established ADAMTS13 haplotypes by analyzing 17 polymorphic intragenic markers. The haplotypes linked to 4143insA were identical in all informative families. Three novel candidate mutations, C347S, P671L and R1060W, as well as the known mutation R507Q, were also identified during the course of the study. We conclude that 4143insA has a common genetic background and is frequent among patients with hereditary ADAMTS13 deficiency in Northern and Central European countries.
Schneppenheim
Reinhard
R
University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Martinistrasse 52, D-20246 Hamburg, Germany. schneppenheim@uke.uni-hamburg.de
Kremer Hovinga
Johanna A
JA
Becker
Tim
T
Budde
Ulrich
U
Karpman
Diana
D
Brockhaus
Wolfgang
W
Hrachovinová
Ingrid
I
Korczowski
Bartosz
B
Oyen
Florian
F
Rittich
Simon
S
von Rosen
Johannes
J
Tjønnfjord
Geir E
GE
Pimanda
John E
JE
Wienker
Thomas F
TF
Lämmle
Bernhard
B
D051722:ADAM Proteins / Q000235:genetics*; D000071120:ADAMTS13 Protein; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005060:Europe / Q000453:epidemiology; D005192:Family Health; D005260:Female; D018703:Founder Effect; D016368:Frameshift Mutation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics
D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human