Volume 20, Issue 1, March 2004

Table of Contents 20-1

Interactions in Gene Encoding Mutations Leading to Cortisone Reductase Deficiency

Draper N, et al. Mutations in the genes encoding 11 þ-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nature Genet 2003;34:434-439.

Abstract

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Draper et al studied a virilized 6-year-old boy with gonadotropin-independent isosexual precocious puberty and two adult women with polycystic ovarian syndrome (PCOS); subjects had low ratios of urinary tetrahydrocortisol to tetrahydrocortisone excretion. These findings were consistent with an autosomal recessive deficiency of cortisone reductase - the enzyme complex that interconverts cortisone (E) and cortisol (F). Cortisone reductase has dual dehydrogenase and oxo-reductase activities depending on the availability of a cofactor - NADP/NADPH. There are two isozymes of 11 ß-hydroxysteroid dehydrogenase (11 þHSD) - hepatic (and adipose tissue) type 1 (E-->F) and renal type 2 (F-->E). In previous studies, as in the present patients, the nucleotide sequence of the 6 exons of 11 b HSD1 (chromosome 1q32-q41, OMIM 604931) was normal. However, in the three subjects in this report mutations were found in intron 3 of 11 ßHSD1 . One woman with PCOS was homozygous for double mutations - insA @ NT 83557 and T?G substitution @ NT 83597, while the second woman and the virilized boy were heterozygous for these mutations. Heterozygous carriers (parents, siblings, general population) of these linked mutations were clinically and biochemically normal. Further examination of the importance of these mutants (or polymorphic variants) revealed that the linked mutations impaired expression of 11 ßHSD1 and biologic activity of the enzyme product. Thus, the investigators concluded that intron 3 of 11 ßHSD1 served as an "intronic enhancer" of the expression of its gene.

Because the activity of 11ßHSD1 requires a co-factor (NADPH) the authors examined NADPH generating systems and identified two mutations in the gene ( H6PD , chromosome 1pter-p36.13, OMIM 138090) encoding the enzyme - hexose-6-phosphate dehydrogenase - that is the principle generator of NADPH in the endoplasmic reticulum in which 11ßHSD1 is located. One mutation in H6PD - heterozygous 29 bp insertion between NTs 620 and 621 was present in the woman who was homozygous for the double mutation in 11 ßHSD1 ; a homozygous mutation - Arg453Gln - was present in the other woman with PCOS and the virilized youth. Both mutations resulted in products with substantially decreased H6PD functional activity.

The investigators concluded that inactivating mutations in both 11 ßHSD1 and H6PD (a total of 3 mutated alleles) must be present in order to result in sufficiently decreased 11ßHSD1 activity to lead to the syndrome of cortisone reductase deficiency. Thus, this disorder is another example of a digenic- triallelic pattern of inheritance as are some forms of the Bardet-Biedl syndrome (OMIM 209000).1,2

Editor's Comment: This manuscript presents yet another cause of gonadotropin-independent pseudoisosexual precocity in boys - cortisone reductase deficiency - indicating the need to measure cortisol, cortisone, and their urinary metabolites in patients with otherwise unexplained hyperandrogenic states. One wonders why females with a similar enzymatic defect do not manifest signs of hyperandrogenism until adulthood. Might there be yet another factor (gene product?) present/absent in young females that preclude early disease expression? It has been suggested that enhanced reductase activity in visceral adipose and perhaps other tissues, with consequent local hypercortisolism, might be associated with the development of visceral obesity and the "dysmetabolic syndrome".3,4 Loss-of-function mutations in the gene 11 ßHSD2 (chromosome 16q12, OMIM 218030) encoding renal 11 ßHSD2 lead to hypertension in the presence of subnormal mineralocorticoid values (the syndrome of "apparent mineralocorticoid excess") because unmetabolized cortisol occupies and activates the mineralocorticoid receptor leading to renal tubular reabsorption of sodium and water and hypervolemia.

Allen W. Root, MD

References - (linked to )

1. Katsanis N, et al. Science 2001;293:2256-2259.
2. GGH 2002; 18:15.
3. Masuzaki H, et al. Science 2001;294:2166-2170.
4. Tiosano D, et al. J Clin Endocrinol Metab 2003;88:379-384.

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