Summary
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.
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Bottema CDK, Koeberl DD, Ketterling RP, Bowie EJW, Taylor SAM, Lillicrap D, Shapiro A, Gilchrist G, Sommer SS (1990) A past mutation of isoleucine 397 is now a common cause of moderate/mild hemophilia B. Br J Haematol 75:212–216
Bottema CDK, Bottema MJ, Ketterling RP, Yoon H-S, Janco RL, Phillips JA III, Sommer SS (1991a) Why does the human factor IX gene have a G+C content of 40 percent? Am J Hum Genet 49:839–850
Bottema CDK, Ketterling RP, Ii S, Yoon H-S, Phillips JA III, Sommer SS (1991b) Missense mutations and evolutionary conservation of amino acids: evidence that many of the amino acids in factor IX function as “spacer” elements. Am J Hum Genet 49:820–838
Eyster ME, Lewis JH, Shapiro SS, Gill F, Kajani M, Prager D, Djerassi I, Rice S, Lusch C, Keller A (1980) The Pennsylvania hemophilia program 1973–1978. Am J Hematol 9:277–286
Giannelli F, Green PM, High KA, Lozier JN, Lillicrap DP, Ludwig M, Olek K, Reitsma PH, Goossens M, Yoshioka A, Sommer S, Brownlee GG (1990) Haemophilia B: database of point mutations and short additions and deletions. Nucleic Acids Res 18:4053–4059
Haldane JBS (1935) The rate of spontaneous mutation of a human gene. J Genet 31:317–326
Hedner U, Davie EW (1989) Introduction to hemostasis and the vitamin K-dependent coagulation factors. In: Scriver CR (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 2107–2134
Ketterling RP, Bottema CDK, Koeberl DD, Ii S, Sommer SS (1991a) T296→M, a common mutation causing mild hemophilia B in the Amish and others: founder effect, variability in factor IX activity assays, and rapid carrier detection. Hum Genet 87:333–337
Ketterling RP, Bottema CDK, Phillips JA III, Sommer SS (1991b) Evidence that descendants of three founders constitute about 25% of hemophilia B in the United States. Genomics 10:1093–1096
Koeberl DD, Bottema CDK, Ketterling RP, Bridge PJ, Lillicrap DP, Sommer SS (1990) Mutations causing hemophilia B: direct estimate of the underlying rates of spontaneous germline transitions, transversions, and deletions in a human gene. Am J Hum Genet 47:202–217
Larsson SA, Nilsson IM, Blomback M (1982) Current status of Swedish hemophiliacs. Acta Med Scand 212:195–200
Logan LL (1988) Hemostasis and bleeding disorders. In: Mazza JJ (eds) Manual of clinical hematology. Little, Brown and Co, Boston Toronto, pp 288–314
Parquet-Gernez A, Mazurier C, Amiral J, Martinoli JL (1984) Assay of factor IX antigen using an enzyme immuno assay. Thromb Res 35:703–712
Roberts HR, Grizzle JE, McLester WD, Penick GD (1968) Genetic variants of hemophilia B: detection by means of a specific PTC inhibitor. J Clin Invest 47:360–365
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Sommer, S.S., Bowie, E.J.W., Ketterling, R.P. et al. Missense mutations and the magnitude of functional deficit: the example of factor IX. Hum Genet 89, 295–297 (1992). https://doi.org/10.1007/BF00220543
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DOI: https://doi.org/10.1007/BF00220543