J Korean Med Sci.  2010 Sep;25(9):1379-1383. 10.3346/jkms.2010.25.9.1379.

Genetic Analyses of the Chimeric CYP11B1/CYP11B2 Gene in a Korean Family with Glucocorticoid-Remediable Aldosteronism

• Lee IS
• Kim SY
• Jang HW
• Kim MK
• Lee JH
• Lee YH
• Jo YS

• KMID: 1785922
• DOI: http://doi.org/10.3346/jkms.2010.25.9.1379

Abstract

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.

Keyword

Hyperaldosteronism; Steroid 11-beta-Hydroxylase; Aldosterone Synthase

MeSH Terms

Adolescent
Aldosterone/blood
Aldosterone Synthase/*genetics
Asian Continental Ancestry Group/*genetics
Dexamethasone/therapeutic use
Family
Female
Glucocorticoids/*therapeutic use
Humans
Hyperaldosteronism/diagnosis/drug therapy/*genetics
Hypertension/etiology
Magnetic Resonance Angiography
Male
Middle Aged
Renin/blood/metabolism
Republic of Korea
Sequence Analysis, DNA
Steroid 11-beta-Hydroxylase/*genetics
Young Adult

Figure

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  Fig. 1 The pedigree of the family showed with the proband indicated by black symbol. Circles, females; squares, males; HTN, hypertension.

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  Fig. 2 Change of plasma renin activity (PRA) and plasma aldosterone concentration before and after normal saline loading test and dexamethasone suppression test. (A) Plasma renin activity (PRA) and plasma aldosterone concentration of proband before and after normal saline loading test. (B) Plasma renin activity (PRA), plasma aldosterone concentration and plasma cortisol of proband before and after dexamethasone suppression test. (C) Plasma renin activity (PRA) and plasma aldosterone concentration of younger brother of proband before and after normal saline loading test. (D) Plasma renin activity (PRA), plasma aldosterone concentration and plasma cortisol of younger brother of proband before and after dexamethasone suppression test. Squares, plasma aldosterone concentration; triangle, plasma renin activity; circles, plasma cortisol.

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  Fig. 3 PCR analysis of DNA extracted from peripheral blood leukocytes of family members. Each subject was represented on the agarose gel. The left and right panels show aldosterone synthase and chimeric gene amplification, respectively.

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  Fig. 4 The breakpoints of "unequal crossing-over" by direct sequencing of PCR product. Nucleotide positions 1507 and 1508 of chimeric gene were identical to intron 2 of specific regions of CYP11B1. Nucleotide positions 46, 61 and 64 of chimeric gene exon 3 were identical with specific regions of CYP11B2. Each bold characteristic on nucleotide sequence of CYP11B1 or CYP11B2 is identical to corresponding nucleotide sequence of chimeric gene CYP11B1/CYP11B2.

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