help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kitanaka, S.
Right arrow Articles by Tanaka, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kitanaka, S.
Right arrow Articles by Tanaka, T.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*OMIM
*Protein*UniGene
*Substance via MeSH
The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 4054-4058
Copyright © 1997 by The Endocrine Society

Original Studies

A New Compound Heterozygous Mutation in the 11ß-Hydroxysteroid Dehydrogenase Type 2 Gene in a Case of Apparent Mineralocorticoid Excess

Sachiko Kitanaka, Noriyuki Katsumata, Ayako Tanae, Itsuro Hibi, Ken-Ichi Takeyama, Hiroaki Fuse, Shigeaki Kato and Toshiaki Tanaka

Department of Endocrinology and Metabolism, National Children’s Medical Research Center (S.K., N.K., T.T.); the Division of Endocrinology and Metabolism, National Children’s Hospital (A.T., I.H.); and the Institute of Molecular and Cellular Biosciences, University of Tokyo (S.K., K.T., H.F., S.K.), Tokyo, Japan

Address all correspondence and requests for reprints to: Dr. Sachiko Kitanaka, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1–1-1 Yayoi, Bunkyo-ku, Tokyo 113, Japan.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Apparent mineralocorticoid excess (AME) characterized by early-onset hypertension and hypokalemia is due to congenital deficiency of 11ß-hydroxysteroid dehydrogenase (11ßHSD). Two isoforms of human 11ßHSD are known, and the type 2 isoform (11ßHSD2) has been recently shown to be responsible for AME. In this study we have analyzed the 11ßHSD2 gene of a Japanese patient with AME. PCR amplification and subsequent nucleotide sequencing of the 11ßHSD2 gene from the patient and his family members revealed that the patient has a compound heterozygous mutation of this gene. In 1 allele, an undescribed single nucleotide transition in codon 208 in exon 3 resulted in a substitution of arginine to histidine (CGC to CAC: R208H). In the other allele, a deletion of 3 nucleotides in codons 337–338 in exon 5 resulted in a substitution of arginine to histidine and a deletion of tyrosine residue (CGCTAT to CAT: R337H, {Delta}Y338), which has been previously shown to abolish 11ßHSD2 enzyme activity. A chloramphenicol acetyltransferase assay-based expression study involving the mineralocorticoid receptor indicated that the novel R208H mutation eliminates the enzymatic activity of 11ßHSD2. From the genetic analysis of 50 healthy subjects, the novel R208H mutation was unlikely to be due to polymorphism. Together, these results indicate that this patient is a compound heterozygote for the mutation in the 11ßHSD2 gene (R208H and R337H, {Delta}Y338) and that these mutations inactivate the 11ßHSD2 function and give rise to clinically manifest AME.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
APPARENT mineralocorticoid excess (AME) is a rare disease characterized by early-onset low renin hypertension combined with hypokalemia despite subnormal levels of all known mineralocorticoids (1; for review, see Ref.2). This disease is due to congenital deficiency of 11ß-hydroxysteroid dehydrogenase (11ßHSD), an enzyme that mediates the conversion of cortisol to cortisone.

The mineralocorticoid receptor (MR) is nonselective in vitro and does not distinguish between cortisol and aldosterone (3, 4). The mechanism by which MR is selectively occupied by aldosterone despite the presence of cortisol in the circulation at a 100-1000 times higher concentration than aldosterone is explained by inactivation of cortisol to cortisone by 11ßHSD (5, 6). Accordingly, in the absence of 11ßHSD activity, cortisol can bind to the MR and act as a mineralocorticoid.

To date, two isoforms of 11ßHSD have been identified. The first isoform, 11ßHSD type 1, is low affinity, NADP dependent, and catalyzes both 11ß-dehydrogenation and the reverse 11-oxoreduction reaction. It is found predominantly in liver, testis, lung, and central nervous systems. The human 11ßHSD type 1 gene on chromosome 1 was cloned in 1991 (7), but analyses of this gene in patients with AME or 11-oxoreductase deficiency gave normal results (8). 11ßHSD type 2 (11ßHSD2) is high affinity, NAD dependent, and catalyzes only 11ß-dehydrogenation (9, 10). The human 11ßHSD2 complementary DNA (cDNA) was cloned in 1994 and is expressed predominantly in kidney, placenta, colon, salivary gland, and fetal tissues (11, 12, 13, 14). The 11ßHSD2 gene is approximately 6.2 kilobases long, consists of five exons, and is located on chromosome 16q22 (15). After cloning of the 11ßHSD2 gene, several missense mutations/deletions that reduce the enzymatic activity of 11ßHSD2 were found in patients with AME (16, 17, 18, 19), indicating that this 11ßHSD2 gene is responsible for AME.

Due to the rare occurrence of AME, few mutations of the 11ßHSD2 gene have been reported. We have analyzed the 11ßHSD2 gene in a patient with typical AME and found that the patient has a novel compound heterozygous mutation in the 11ßHSD2 gene that inactivates 11ßHSD2 function.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The patient is a Japanese male with AME who has been previously reported (20). Briefly, he was born with intrauterine growth retardation and an elevated serum creatine phosphokinase level. He was studied at 2 yr of age because of polyuria and polydipsia lasting for 1 yr and was found to have hypokalemic alkalosis and sustained hypertension. His PRA and aldosterone levels were always low, and the ratio of urinary tetrahydrocortisol (THF) plus allotetrahydrocortisol (aTHF) to that of tetrahydrocortisone (THE) was very high (43.7 and 17.4 in two determinations). He has been successfully treated with a combination of spironolactone and nifedipine.

The patient was the second child of unrelated parents. His father comes from Tochigi prefecture (in central Japan), and his mother comes from Gotou Island of Nagasaki prefecture (in southern Japan). His father, mother, and elder sister were normotensive, normokalemic, and had normal ratios of urinary THF plus aTHF/THE (2.1, 2.1, and 1.6, respectively).

DNA amplification and sequence analysis of the 11ßHSD2 gene

The genomic DNAs of all family members were extracted from peripheral white blood cells. PCR was performed to amplify the entire coding region of the 11ßHSD2 gene (exons 1–5) using primer sets previously described (16). Reaction mixtures were modified and contained 200 ng genomic DNA, 25 pmol of each primer, 10 nmol of each deoxy-NTP, 2.5 U Taq DNA polymerase (Takara Shuzo, Kyoto, Japan), and its standard buffer in a total volume of 100 µL. Amplified gene fragments were purified by agarose gel electrophoresis, and each PCR product was sequenced directly using modified T7 DNA polymerase (Sequenase 7-deaza-deoxy-GTP Sequencing Kit, U.S. Biochemical Corp., Cleveland, OH) with the same primers as those used for PCR. Another internal primer in exon 5, 5'-AAGGACTACATCGAGCACTTGCA-3' (sense), was used to sequence the middle part of exon 5. Subcloning of the PCR products amplified from exons 3 and 5 of the patient was performed using the TA cloning kit (Invitrogen, San Diego, CA), and the sequencing was performed as described above.

Restriction analysis

The mutation in exon 3 found in the patient and his family members, which eliminates an FspI restriction site, was confirmed by digestion of PCR products with the restriction enzyme. The PCR products from 50 endocrinologically normal subjects were similarly analyzed to exclude polymorphism of the gene. Both normal and mutant alleles of the patient subcloned to a vector were separately analyzed in the same way.

Construction of plasmids

Full-length human 11ßHSD2 cDNA (a gift from Dr. Z. S. Krozowski) was subcloned into the mammalian expression vector pcDNA3 (Invitrogen). An R208H mutation in 11ßHSD2 cDNA was introduced by PCR using oligonucleotides containing the desired change (21). The cDNA of the rat MR encoding the DEF regions (nucleotides 2014–2946), which include the ligand-binding domain (E domain) and possess a ligand-induced transactivation function 2 (AF-2), was generated by reverse transcription-PCR from rat kidney messenger ribonucleic acid and subcloned into pM vector (Clontech Laboratories, Palo Alto, CA) to create pGAL-MR(DEF) that expresses a chimeric MR(DEF) protein fused to the DNA-binding domain of a yeast transcription factor, GAL4. All of the constructs were sequence verified to ensure introduction of the desired mutation and the absence of extraneous mutations. The construction of the GAL4-responsive reporter plasmid 17M2-G-CAT containing chloramphenicol acetyltransferase (CAT) gene has been described previously (22).

Cell transfection and CAT assay

HeLa cells were maintained in DMEM without phenol red supplemented with 5% FCS stripped with dextran-coated charcoal. Transfection was performed by means of calcium phosphate coprecipitation when cells were 40–60% confluent in 9-cm petri dishes. The reporter plasmid 17M2-G-CAT (2 µg) and pGAL-MR(DEF) (2 µg) were cotransfected with 2 µg empty pcDNA3 vector, wild-type 11ßHSD2 expression vector, or 11ßHSD2-R208H expression vector. In addition, 3 µg pCH110 (Pharmacia, Uppsala, Sweden), a ß-galactosidase expression plasmid, was always included in the transfection mixture and was used as an internal control to normalize for variations in transfection efficiency. Bluescribe M13+ (Stratagene) was used as a carrier to adjust the total amount of transfected DNAs to 20 µg. After incubation with calcium phosphate-precipitated DNAs for 20 h, the cells were fed with fresh medium, and then cortisol was added to the culture medium. After incubation for an additional 24 h, cell extracts were prepared by freeze-thawing and used for CAT assays after normalizing for ß-galactosidase activity as described previously (23, 24).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
11ßHSD2 gene sequence

To analyze the 11ßHSD2 gene, we used a combination of primer sets and amplified the entire coding region from the genomic DNAs obtained from the patient and his family members as well as that from normal subjects. The PCR products amplified from the patient were sequenced directly, which revealed two heterozygous mutations (Fig. 1Go). One mutation was a G to A transition in the second nucleotide in codon 208 (exon 3) that resulted in a substitution of arginine to histidine (CGC to CAC: R208H). The other was a deletion of three nucleotides (GCT) in codons 337–338 (exon 5) that resulted in a substitution of arginine to histidine and a deletion of tyrosine (CGCTAT to CAT: R337H, {Delta}Y338). When the PCR fragments were sequenced after subcloning into a vector plasmid, the latter mutation in exon 5 was detected in five of the eight clones examined, whereas DNA sequence in the other three clones was normal. The possibility that the mutation was caused by PCR artifact was excluded by repeat PCR and direct sequencing in both directions as well as by the identical results obtained from subcloned PCR products. No other mutations were found in the exons of the 11ßHSD2 gene amplified from the patient.



View larger version (39K):
[in this window]
[in a new window]
  		Figure 1. Sequence analysis of 11ßHSD type 2 gene in the AME patient and his father, mother, and elder sister. The family pedigree of this patient is shown in the upper panel. Sequence analysis of the 11ßHSD type 2 gene of the patient revealed a codon 208 mutation (CGC to CAC: R208H) in one allele identified by direct sequencing (middle upper panel) and a codon 337–338 mutation (CGCTAT to CAT: R337H, {Delta}Y338) in the other allele identified by both direct sequencing (middle lower panel) and sequencing after subcloning (lower panel). The nonaffected father and sister are carriers of the codon 208 mutation, and the mother is a carrier of the codon 337–338 mutation. Stars indicate mutated nucleotides/amino acids. The arrow indicates the proband.

 
The PCR-amplified 11ßHSD2 gene from patient’s family was also analyzed by direct sequencing (Fig. 1Go). The results indicated that the father and the sister had a heterozygous mutation for R208H, whereas codons 337–338 of both subjects were normal. The patient’s mother had heterozygous mutation for R337H, {Delta}Y338, whereas codon 208 was normal.

Restriction analysis

We confirmed the 1-bp transition in codon 208 (CGC to CAC) using the restriction enzyme FspI, which recognizes the sequence TGCGCA (codon 208 is underlined) in the normal allele. FspI digestion of the PCR products amplified from exons 3 and 4 of the normal allele should produce 2 fragments, 276 and 123 bp, whereas that of the mutated allele remains as an undigested 399-bp fragment. FspI digestion of the PCR products amplified from the patient, the father, and the sister produced 3 fragments of 399, 276, and 123 bp, whereas digestion of the PCR product amplified from the patient’s mother produced 2 fragments of 276 and 123 bp (Fig. 2Go). Thus, the patient and his unaffected father and sister are heterozygous, and his mother is normal homozygous for the mutation in codon 208. FspI digestion of exon 3–4 PCR products from 50 endocrinologically normal subjects invariably resulted in 2 fragments, 276 and 123 bp, indicating that the CGC to CAC transition in codon 208 is not a polymorphism.



View larger version (40K):
[in this window]
[in a new window]
  		Figure 2. Detection of G to A substitution in codon 208 of the 11ßHSD2 gene by FspI digestion. Exons 3–4 of the 11ßHSD2 gene were amplified from the patient, family members, a normal control, and subcloned normal and mutant alleles of the patient. The amplified PCR products (399 bp) were digested with FspI and run on a 2% agarose gel. Digestion of the normal PCR products should produce 276- and 123-bp fragments, whereas that of the mutated PCR products a single 399-bp fragment. The molecular size marker, HaeIII-digested {phi}X174, is shown on the left.

 
11ßHSD2 expression study

To examine whether the R208H mutation affects the enzymatic activity of 11ßHSD2, wild-type and mutated 11ßHSD2 were overexpressed in HeLa cells, and their in vivo enzymatic activity to convert cortisol into cortisone was assessed by examining the cortisol-induced transcriptional activation function by MR-AF-2. By using the GAL4 DNA-binding domain-MR ligand-binding domain fusion construct [pGAL-MR(DEF)], we avoided potential interference by endogenous factors targeting the cognate DNA-binding site of MR. The enzymatic function of 11ßHSD2 was analyzed essentially as described by Warriar et al., who studied 11ßHSD1 (25). In the absence of overexpressed 11ßHSD2, the CAT activity representing the ligand-induced transactivation of MR-AF-2 increased with the increasing concentration of cortisol (Fig. 3Go) and aldosterone (data not shown), and a cortisol concentration as low as 10-8 mol/L could stimulate MR-AF-2 transcriptional activation. However, when wild-type 11ßHSD2 was coexpressed in HeLa cells, efficient cortisol-induced transcriptional activation was observed only at concentrations higher than 10-6 mol/L. This indicates that the overexpressed 11ßHSD2 effectively converted cortisol to inactive cortisone. In contrast, no enzymatic inactivation of cortisol was seen with 11ßHSD2 R208H mutant, as transcriptional activation by MR-AF-2 was induced even at 10-8 mol/L cortisol concentration (Fig. 3Go, A and B). We could reproduce similar results using COS-1 cells (data not shown). These results suggest that R208H mutation abolishes the enzymatic activity of 11ßHSD2.



View larger version (24K):
[in this window]
[in a new window]
  		Figure 3. The R208H mutation abolishes the enzymatic activity of 11ßHSD2. HeLa cells were cotransfected with 2 µg pGAL-MR(DEF), 2 µg 17 M2-G-CAT, and 2 µg empty pcDNA3 (open triangle), wild-type 11ßHSD2 (open square), or 11ßHSD2 R208H (closed circle) expressing plasmid. Cells were treated with ethanol (-) or 10-5–10-9 mol/L cortisol for 24 h as indicated. CAT assays were performed as described in Materials and Methods. A representative CAT assay result is shown in A and is quantitatively summarized in B.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To date, 10 mutations of 11ßHSD2 gene abnormalities have been reported in 15 families (18 patients) with AME (16, 17, 18, 19) (Fig. 4Go). In the present study we demonstrated a new compound heterozygous mutation of 11ßHSD2 gene in a Japanese patient affected with AME. Interestingly, all mutations, including ours, are clustered in exons 3–5, suggesting that this region contains residues important for 11ßHSD2 enzyme function or that this region has an increased tendency to develop mutations.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 4. Diagrammatic presentation of 11ßHSD2 gene structure. Exons are numbered, and untranslated regions are shaded. Bold letters indicate compound heterozygous mutations. A compound heterozygous mutation found in our patient is indicated above. The positions of all mutations reported in AME patients are shown below.

 
The G to A transition in the second nucleotide of codon 208 resulted in a substitution of arginine to histidine (R208H) in 1 allele of the patient. According to our restriction analysis, there were no mutations in codon 208 among 50 normal people, suggesting that this is not a polymorphism. Furthermore, the expression study demonstrated that the R208H mutation totally abolishes the enzymatic activity of 11ßHSD2, thus indicating that this is unequivocally an inactivating mutation. Another type of missense mutation in codon 208 has been reported in 2 AME families, 1 native North American (16) and the other from Oman (17); both were homozygous for arginine (CGC) to cysteine (TGC) substitution (R208C). Considering that this arginine residue is highly conserved within human, rat, mouse, and sheep 11ßHSD2 (14, 26, 27, 28), these findings underscores the critical role of this arginine residue in 11ßHSD2 function.

The other mutation found in our patient was a three-nucleotide deletion in codons 337–338, resulting in a substitution of arginine to histidine and a deletion of tyrosine (R337H, {Delta}Y338). Exactly the same homozygous mutation has been found in three other families, two from India and one from Iran (16, 17). In addition, the results of expression study indicated that 11ßHSD2 harboring this mutation has no detectable enzyme activity (16). Thus, it is highly likely that this mutation as well as the R208H mutation is the cause of the enzyme defect in this patient.

Among the nonaffected family members, the patient’s father and sister carried only the R208H mutation, whereas the mother carried only the R337H, {Delta}Y338 mutation. These heterozygous carriers were totally normal for blood pressure, serum potassium, and urinary THF plus aTHF/THE ratio. This indicates that the heterozygotes of 11ßHSD2 gene mutation are clinically indistinguishable from normal subjects, which is consistent with the autosomal recessive inheritance of this disease.

The affected AME patients in 14 of 15 families were all homozygotes for their 11ßHSD2 mutations (16, 17, 18, 19). The only compound heterozygote was an Irish-American, whose 11ßHSD2 gene had an 11-bp deletion giving rise to a premature termination codon as a result of a frame shift and a 9-bp deletion eliminating the catalytic site (16). On the other hand, most of the homozygous mutations were missense mutations or 1- to 3-bp deletions, some of which do not totally abolish the enzyme activity. Accordingly, it was suggested that an identical mutation on both alleles is required for clinical manifestation of the disease and that a subject who is a compound heterozygote may have a very mild disease that goes undetected (17, 29). Our patient is a typical case of AME with early presentation of hypertension, hypokalemia, and high THF plus aTHF/THE ratio, together with intrauterine growth retardation, which proved to be a common feature of this disease (19, 20). The finding that this patient had a compound heterozygous mutation, one missense mutation and one 3-bp deletion, verified that a compound heterozygous mutation in the 11ßHSD2 gene can be the cause of AME. It is also clear that patients with homozygous and compound heterozygous mutations are indistinguishable by clinical studies.


   Acknowledgments
 
The authors thank Dr. Z. S. Krozowski for generous gift of 11ßHSD2 cDNA. We also thank Mr. T. Kitamoto, Ms. A. Miyokawa, and Ms. M. Shimizu for their technical assistance, and Dr. C. Kitanaka for critically reading the manuscript and for helpful comments.

Received July 17, 1996.

Revised April 16, 1997.

Accepted May 23, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Ulick S, Levine LS, Gunczler P, et al. 1979 A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab. 49:757–764.[Abstract/Free Full Text]
  2. Shackleton CHL, Stewart PM. 1990 The hypertension of apparent mineralocorticoid excess syndrome. In: Biglieri EG, Melby JC, eds. Endocrine hypertension. New York: Raven Press; 155–173.
  3. Krozowski ZS, Funder JW. 1983 Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity. Proc Natl Acad Sci USA. 80:6056–6060.[Abstract/Free Full Text]
  4. Arriza JL, Weinberger C, Derelli G, et al. 1987 Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science. 237:268–275.[Abstract/Free Full Text]
  5. Edwards CRW, Stewart PM, Burt D, et al. 1988 Localization of 11ß-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor. Lancet. 2:986–989.[CrossRef][Medline]
  6. Funder JW, Pearce PT, Smith R, Smith AI. 1988 Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science. 242:583–585.[Abstract/Free Full Text]
  7. Tannin GM, Agarwal AK, Monder C, New MI, White PC. 1991 The human gene for 11ß-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization. J Biol Chem. 266:16653–16658.[Abstract/Free Full Text]
  8. Nikkilä H, Tannin GM, New MI, et al. 1993 Defects in the HSD11 gene encoding 11ß-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency. J Clin Endocrinol Metab. 77:687–691.[Abstract]
  9. Brown RW, Chapman KE, Edwards CRW, Seckl JR. 1993 Human placental 11ß-hydroxysteroid dehydrogenase: evidence for partial purification of a distinct NAD-dependent isoform. Endocrinology. 132:2614–2621.[Abstract/Free Full Text]
  10. Stewart PM, Murry BA, Mason JI. 1994 Human kidney 11ß-hydroxysteroid dehydrogenase is a high affinity nicotinamide adenine dinucleotide-dependent enzyme and differs from the cloned type I isoform. J Clin Endocrinol Metab. 79:480–484.[Abstract]
  11. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. 1994 Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 105:R11–R17.
  12. Whorwood CB, Mason JI, Rickeetts ML, Howie AJ, Stewart PM. 1995 Detection of human 11ß-hydroxysteroid dehydrogenase isoforms using RT-PCR and localization of the type 2 isoform to renal collecting ducts. Mol Cell Endocrinol. 110:R7–R12.
  13. Krozowski ZS, Maguire JA, Stein-Oakley AN, Dowling J, Smith RE, Andrews RK. 1995 Immunohistochemical localization of the 11ß-hydroxysteroid dehydrogenase type II enzyme in human kidney and placenta. J Clin Endocrinol Metab. 80:2203–2209.[Abstract]
  14. Stewart PM, Murry BA, Mason JI. 1994 Type 2 11ß-hydroxysteroid dehydrogenase in human fetal tissues. J Clin Endocrinol Metab. 78:1529–1532.[Abstract]
  15. Agarwal AK, Rogerson FM, Mune T, White PC. 1995 Gene structure and chromosomal localization of the human HSD11K gene encoding the kidney (type 2) isozyme of 11ß-hydroxysteroid dehydrogenase. Genomics. 29:195–199.[CrossRef][Medline]
  16. Mune T, Rogerson FM, Nikkilä H, Agarwal AK, White PC. 1995 Human hypertension caused by mutations in the kidney isozyme of 11ß-hydroxysteroid dehydrogenase. Nat Genet. 10:394–399.[CrossRef][Medline]
  17. Wilson RC, Harbison MD, Krozowski ZS, et al. 1995 Several homozygous mutations in the gene for 11ß-hydroxysteroid dehydrogenase type 2 in patients with apparent mineralocorticoid excess. J Clin Endocrinol Metab. 80:3145–3150.[Abstract]
  18. Wilson RC, Krozowski ZS, Obeyesekere VR, et al. 1995 A mutation in the HSD11B2 gene in a family with apparent mineralocorticoid excess. J Clin Endocrinol Metab. 80:2263–2266.[Abstract]
  19. Stewart PM, Krozowski ZS, Gupta A, et al. 1996 Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11 beta-hydroxysteroid dehydrogenase type 2 gene. Lancet. 347:88–91.[CrossRef][Medline]
  20. Kitanaka S, Tanae A, Hibi I. 1996 Apparent mineralocorticoid excess due to 11ß-hydroxysteroid dehydrogenase deficiency: a possible cause of intrauterine growth retardation. Clin Encodrinol (Oxf). 44:353–359.[CrossRef][Medline]
  21. Higuchi R. 1990 Recombinant PCR. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ, eds. PCR protocols. San Diego: Academic Press; 177–183.
  22. Webster NJG, Green S, Jin JR, Chambon P. 1988 The hormone binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function. Cell. 54:199–207.[CrossRef][Medline]
  23. Kato S, Tora L, Yamauchi J, Masushige S, Bellard M, Chambon P. 1992 A far upstream estrogen element of the ovalbumin gene contains several half-palindromic 5'-TGACC-3' motifs acting synergistically. Cell. 68:731–742.[CrossRef][Medline]
  24. Ebihara K, Masuhiro Y, Kitamoto T, et al. 1996 Intron retention generates a novel isoform of the murine vitamin D receptor that acts in a dominant negative way on the vitamin D signaling pathway. Mol Cell Biol. 16:3393–3400.[Abstract]
  25. Warriar N, Page N, Govindan MV. 1994 Transcription activation of mouse mammary tumor virus-chloramphenicol acetyltransferase: a model to study the metabolism of cortisol. Biochemistry. 33:12837–12843.[CrossRef][Medline]
  26. Zhou MY, Gomez-Sanchez EP, Cox DL, Cosby D, Gomes-Sanchez DE. 1995 Cloning, expression, and tissue distribution of the rat nicotinamide adenine dinucleotide-dependent 11ß-hydroxysteroid dehydrogenase. Endocrinology. 136:3729–3734.[Abstract]
  27. Cole TJ. 1995 Cloning of the mouse 11ß-hydroxysteroid dehydrogenase type 2 gene: tissue-specific expression and localization in distal convoluted tubules and collecting ducts of the kidney. Endocrinology. 136:4693–4696.[Abstract]
  28. Agarwal AK, Mune T, Monder C, White PC. 1994 NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase-cloning and characterization of cDNA from sheep kidney. J Biol Chem. 269:25959–25962.[Abstract/Free Full Text]
  29. Funder JW. 1996 11ß-Hydroxysteroid dehydrogenase: new answers, new questions. Eur J Endocrinol. 134:267–268.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Am. Soc. Nephrol.Home page
G. Morineau, V. Sulmont, R. Salomon, B. Fiquet-Kempf, X. Jeunemaitre, J. Nicod, and P. Ferrari
Apparent Mineralocorticoid Excess: Report of Six New Cases and Extensive Personal Experience
J. Am. Soc. Nephrol., November 1, 2006; 17(11): 3176 - 3184.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. M. Paterson, J. R. Seckl, and J. J. Mullins
Genetic manipulation of 11{beta}-hydroxysteroid dehydrogenases in mice
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R642 - R652.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
N. Draper and P. M Stewart
11{beta}-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action
J. Endocrinol., August 1, 2005; 186(2): 251 - 271.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. Lin-Su, P. Zhou, N. Arora, B. P. Betensky, M. I. New, and R. C. Wilson
In Vitro Expression Studies of a Novel Mutation {Delta}299 in a Patient Affected with Apparent Mineralocorticoid Excess
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2024 - 2027.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Quinkler and P. M. Stewart
Hypertension and the Cortisol-Cortisone Shuttle
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2384 - 2392.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. A. Carvajal, A. A. Gonzalez, D. G. Romero, A. Gonzalez, L. M. Mosso, E. T. Lagos, M. d. P. Hevia, M. P. Rosati, T. O. Perez-Acle, C. E. Gomez-Sanchez, et al.
Two Homozygous Mutations in the 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Gene in a Case of Apparent Mineralocorticoid Excess
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2501 - 2507.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
C.-B. Lanz, M. Causevic, C. Heiniger, F. J. Frey, B. M. Frey, and M. G. Mohaupt
Fluid Shear Stress Reduces 11{beta}-Hydroxysteroid Dehydrogenase Type 2
Hypertension, January 1, 2001; 37(1): 160 - 169.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Kitanaka, A. Murayama, T. Sakaki, K. Inouye, Y. Seino, S. Fukumoto, M. Shima, S. Yukizane, M. Takayanagi, H. Niimi, et al.
No Enzyme Activity of 25-Hydroxyvitamin D3 1{alpha}-Hydroxylase Gene Product in Pseudovitamin D Deficiency Rickets, Including That with Mild Clinical Manifestation
J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4111 - 4117.
[Abstract] [Full Text]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. I. New and R. C. Wilson
Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess
PNAS, October 26, 1999; 96(22): 12790 - 12797.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
B. S. Nunez, F. M. Rogerson, T. Mune, Y. Igarashi, Y. Nakagawa, G. Phillipov, A. Moudgil, L. B. Travis, M. Palermo, C. Shackleton, et al.
Mutants of 11{beta}-Hydroxysteroid Dehydrogenase (11-HSD2) With Partial Activity : Improved Correlations Between Genotype and Biochemical Phenotype in Apparent Mineralocorticoid Excess
Hypertension, October 1, 1999; 34(4): 638 - 642.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. C. Wilson, S. Dave-Sharma, J.-Q. Wei, V. R. Obeyesekere, K. Li, P. Ferrari, Z. S. Krozowski, C. H. L. Shackleton, L. Bradlow, T. Wiens, et al.
A genetic defect resulting in mild low-renin hypertension
PNAS, August 18, 1998; 95(17): 10200 - 10205.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Dave-Sharma, R. C. Wilson, M. D. Harbison, R. Newfield, M. R. Azar, Z. S. Krozowski, J. W. Funder, C. H. L. Shackleton, H. L. Bradlow, J.-Q. Wei, et al.
Examination of Genotype and Phenotype Relationships in 14 Patients with Apparent Mineralocorticoid Excess
J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2244 - 2254.
[Abstract] [Full Text]

Home page
 NEJMHome page
S. Kitanaka, K.-i. Takeyama, A. Murayama, T. Sato, K. Okumura, M. Nogami, Y. Hasegawa, H. Niimi, J. Yanagisawa, T. Tanaka, et al.
Inactivating Mutations in the 25-Hydroxyvitamin D3 1{alpha}-Hydroxylase Gene in Patients with Pseudovitamin D-Deficiency Rickets
N. Engl. J. Med., March 5, 1998; 338(10): 653 - 662.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kitanaka, S.
Right arrow Articles by Tanaka, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kitanaka, S.
Right arrow Articles by Tanaka, T.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*OMIM
*Protein*UniGene
*Substance via MeSH

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals