Genetics

The AT gene, located on chromosome 1, is comprised of seven exons spanning 13.4 kb from the transcription start to the polyadenylation.  Isolation of the AT gene led to a molecular analysis of the mutations associated with hereditary AT deficiency.  Data on frequencies of AT allelic variants have been tabulated and a catalog of AT mutations responsible for Types I and II deficiency is now available.

The mutations underlying HD have often been classified according to 2 types.  Type I deficiencies have reduced levels (~ 50%) of immunologically and functionally determined antithrombin.  Type I HD is a true physiologic deficiency state.  The molecular basis of this disorder is either deletion of a large segment of the gene, or the occurrence of other alterations such as nonsense mutations, missense mutations, or base substitutions at splice sites.

Type II deficiency applies to cases in which the functional AT is reduced (~ 50% in heterozygotes) and approximately half the AT antigen is provided by a variant protein.  These deficiencies are produced by discrete molecular defects within the AT protein and generally result from a point mutation in the AT gene.  The variants may have functional abnormalities of the reactive site or the heparin binding site.  In other cases, it has been suggested that the mutation causes multiple functional abnormalities affecting the reactive site, the heparin binding site and the plasma concentration.  Type II variants affecting heparin binding are not associated with an increased risk of thrombosis, unless the individual is homozygous.  Type II mutations affecting the reactive site exhibit abnormal binding of AT to thrombin and can exhibit very high incidence of thrombosis.

What is the prevalence of Type 1 HD?

Divider Imagery

References

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