Missense mutations and the magnitude of functional deficit: the example of factor IX

Steve S. Sommer, E. J.W. Bowie, Rhett P. Ketterling, Cynthia D.K. Bottema

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Some missense changes are compatible with normal protein function while others compromise essential aspects of protein maturation, specific activity, or stability. For those missense changes that alter function in the intact organism, how likely is it for the mutated protein to retain appreciable residual activity? By genetic analysis of patients with hemophilia B of known severity, this question can be addressed for missense mutations that reduce factor IX activity by fourfold or more below the average. We estimate that missense changes cause only 59% of moderate and severe disease, but these mutations are almost always (95%) of independent origin. In contrast, missense mutations are found in virtually all (97%) families with mild disease, but only a minority of these (41%) are of independent origin. From the aggregate data, we estimate that most (71%) of the independent deleterious missense mutations cause at least a 20-fold decrease in factor IX activity.

Original languageEnglish (US)
Pages (from-to)295-297
Number of pages3
JournalHuman genetics
Issue number3
StatePublished - May 1992

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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