Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase

Abstract

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

“…PA patients can be classified into those with aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism, or familial hyperaldosteronism (FH), which is further divided into FH types 1-3 (FHI-FHIII) (5). In 1992, FHI was shown to result from a gene fusion of cytochrome P450, family 11, subfamily B, polypeptide 2 (CYP11B2: aldosterone synthase) and cytochrome P450, family 11, subfamily B, polypeptide 1 (CYP11B1; cortisol synthase) that resulted in zona fasciculata (ZF) expression of CYP11B2 and excess aldosterone production (6). For almost two decades after the original report, no other genetic abnormalities were identified in the other forms of PA.…”

O espectro das síndromes de hipertensão esteróide na infância e adolescência

“…Uma enzima distinta, a CYP11B2 (aldosterona sintetase), presente exclusivamente na ZG (52), converte B em 18-OHB e em aldosterona, e pode, em condições especiais como o HASD/HFI, sintetizar 18-OHF e 18-oxoF a partir do cortisol. O gene responsável pela expressão da aldosterona sintetase, CYP11B2, está localizado no mesmo cromossomo 8, a aproximadamente 40 kilobases do gene CYP11B1 (53,54). Ambos têm alto grau de homologia, sendo 95% similares nas suas seqüências exônicas e de aminoácidos e 90%, nas suas seqüências intrônicas.…”

“…Indivíduos com HASD/HFI apresentam um gene mutante ou "quimérico", formado pela combinação do CYP11B1 com o CYP11B2, resultando na expressão ectópica da enzima aldosterona sintetase na ZF, passando a ser regulada apenas pelo ACTH, e não mais pela angiotensina (53,54). Assim, a formação excessiva de aldosterona na ZF controlada pelo ACTH, acompanha o ritmo nictemeral do cortisol e leva a supressão da APR, hipertensão e hipocalemia.…”

Monogenic forms of mineralocorticoid hypertension: insights into the pathogenesis of ‘essential’ hypertension?

“…So long as the breakpoint of the hybrid gene is in or 5Ј to exon 4, the resultant protein can synthesise aldosterone but is under the regulatory control by ACTH, explaining the phenotype of GRA. 20,21,25 In an adrenal gland removed from an affected case of GRA, this chimeric gene was indeed shown to be expressed throughout the adrenal cortex and was stimulated by ACTH in vitro. 15 This abnormal gene duplication can be detected by Southern blotting, 26 or by faster and cheaper long polymerase chain reaction (PCR) 27 allowing for direct genetic screening for this disorder and prenatal diagnosis.…”

“…However, like aldosterone itself, these 18-hydroxylated steroids were also shown to be ACTH-regulated and suppressed by dexamethasone, suggesting aberrant expression and regulation of 18-hydroxylase in GRA. 17,18 The molecular basis for GRA was first identified by Lifton and colleagues in 1992, 20,21 following the cloning and characterisation of the P450 11␤-hydroxylase genes involved in the final pathways of glucocorticoid and mineralocorticoid biosynthesis 22,23 ( Figure 1). 11␤-hydroxylase (CYP11B1) is responsible for the conversion of 11-deoxycortisol to cortisol and, as such is regulated by ACTH.…”