Taking a Third Strike

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Science  25 Jul 2003:
Vol. 301, Issue 5632, pp. 438
DOI: 10.1126/science.301.5632.438b

Sickle cell anemia is the classic example of a monogenic disease, in which a mutation in the gene encoding the β chain of hemoglobin produces an altered protein that is directly responsible for the loss of red cells. At the other end of the spectrum are multifactorial diseases, such as diabetes and asthma, which are caused by mutations in several genes in combination with environmental factors.

Draper et al. document a rare instance of a triallelic digenic condition resulting in cortisone reductase deficiency (CRD). Within the lumen of the endoplasmic reticulum, two enzymes, hexose-6-phosphate dehydrogenase (H6PDH) and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), cooperate to drive the reduction of cortisone to cortisol. Of three CRD patients, two were homozygous for a mutation in H6PDH and heterozygous for a mutation in 11β-HSD1, whereas the third exhibited the converse genotype. In contrast, individuals bearing the same mutation in both copies of the gene encoding either enzyme (but without the third mutation) were unaffected. The interaction of these loci can be described as summed reductions in pathway flux that cross the threshold from health into disease. — GJC

Nature Genet. 10.1038/ng1214 (2003).

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