What is the role of genetics in the pathophysiology of antithrombin III (ATIII) deficiency?

Updated: Mar 04, 2020
  • Author: James L Harper, MD; Chief Editor: Hassan M Yaish, MD  more...
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Numerous discrete point mutations of the antithrombin gene have been identified. [5, 6] The type I deficiency is the most common phenotype however.

Two defects, wibble and wobble, have been characterized as resulting in substitutions of a single amino acid at the beginning of the beta sheet of the peptide. Substitutions that result in polar amino acids in this location result in decreased activity and survival of the enzyme (Wibble), whereas others cause amino acid substitutions and result in less severe decreases. Clinically, the Wibble gene is associated with a greater risk of thrombosis early in life (second decade).

Other regions of the gene (eg, the "shutter" region) are also associated with clinically significant thrombosis. The shutter region of the antithrombin III protein is centrally located near the "A" B sheet and facilitates opening and closing of the enzyme's active site. These examples are all part of the conformational diseases that may occur in all SERPIN class enzymes (see Alpha-1 Antitrypsin Deficiency).

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