title: A common origin of the 4143insA ADAMTS13 mutation.
abstract: 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.
authors.affiliation: University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Martinistrasse 52, D-20246 Hamburg, Germany. schneppenheim@uke.uni-hamburg.de
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Kremer Hovinga
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.forename: Ulrich
authors.initials: U
authors.lastname: Budde
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brockhaus
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hrachovinová
authors.forename: Bartosz
authors.initials: B
authors.lastname: Korczowski
authors.forename: Florian
authors.initials: F
authors.lastname: Oyen
authors.forename: Simon
authors.initials: S
authors.lastname: Rittich
authors.forename: Johannes
authors.initials: J
authors.lastname: von Rosen
authors.forename: Geir E
authors.initials: GE
authors.lastname: Tjønnfjord
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lämmle
mesh_terms: 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
chemical_list: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human