Cortisone-reductase deficiency associated with heterozygous mutations in 11β-hydroxysteroid dehydrogenase type 1

Abstract

In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum. Loss of this activity results in a disorder termed cortisone reductase deficiency (CRD), typified by increased cortisol clearance and androgen excess. To date, only mutations in H6PD, which encodes an enzyme supplying cofactor for the reaction, have been identified as the cause of disease. Here we examined the HSD11B1 gene in two cases presenting with biochemical features indicative of a milder form of CRD in whom the H6PD gene was normal. Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1. The R137C mutation disrupts salt bridges at the subunit interface of the 11β-HSD1 dimer, whereas K187N affects a key active site residue. On expression of the mutants in bacterial and mammalian cells, activity was either abolished (K187N) or greatly reduced (R137C). Expression of either mutant in a bacterial system greatly reduced the yield of soluble protein, suggesting that both mutations interfere with subunit folding or dimer assembly. Simultaneous expression of mutant and WT 11β-HSD1 in bacterial or mammalian cells, to simulate the heterozygous condition, indicated a marked suppressive effect of the mutants on both the yield and activity of 11β-HSD1 dimers. Thus, these heterozygous mutations in the HSD11B1 gene have a dominant negative effect on the formation of functional dimers and explain the genetic cause of CRD in these patients.

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

“…However, the homodimeric structure of the enzyme could make possible a dominant negative effect of the mutations, although these are rare in metabolic diseases. However, some forms of hypophosphatasia (MIM 146300, 241500, 241510) and also of cortisone reductase deficiency (MIM 604931) can be transmitted in a dominant manner and in these cases the mutations can exhibit a dominantnegative effect by inhibiting the enzymatic activity of the heterodimer (Lawson et al 2011;Lia-Baldini et al 2001). …”

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…These subjects are heterozygous for mutations in the coding sequence of HSD11B1. One mutation (Arg137Cys) disrupts salt bridges at the dimerization interface and reduces enzyme activity, and the other (Lys187Asn) interrupts the active site and not surprisingly abolishes 11␤-HSD1 activity altogether (393). The mutants appear to exert dominant negative effects on the normal allelic product.…”

“…Interestingly, mutations which inactivate 11␤-HSD1 itself, cortisone reductase deficiency (393), produce a milder pheno-type because, although 11␤-reductase activity is lost, there is no "gain" of dehydrogenase activity which occurs with H6PDH deficiency.…”

“…Sadly, no data on the metabolic phenotype, if any, of subjects with HSD11B1 mutations in cortisone reductase deficiency are available (393). However, a unique patient with "apparent cortisone reductase deficiency" who developed pituitary ACTH-dependent Cushing's disease presenting with secondary amenorrhea illustrates well the importance of 11␤-reductase.…”

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

“…A CRD genetikai eredetének nagyfokú heterogenitására utal Lawson és munkatársai vizsgálata, akik két kortizolreduktáz-hiánnyal diagnosztizált gyermekben HSD11B1 génmutációkat azonosítottak, de a H6PD génben nem mutattak ki eltérést. Mindkét HSD11B1 génmutáció (R137C és K187N) aminosav cserével járó mutációnak bizonyult, amelyek gátolják az enzim megfelelő működését [16].…”