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Monogenic Hypertension Thitisak Kitthaweesin MD..

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1 Monogenic Hypertension Thitisak Kitthaweesin MD.

2 Monogenic Hypertension HT is a major public-health problem Molecular pathogenesis in most patients remains poorly understand Genetic factors …known to play a role in determining inter-individual variation in BP.

3 Monogenic Hypertension There are mutations and polymorphisms that altering BP in human All the gene are involve directly or indirectly in control of Na reabsorption Mutations have been found in monogenic hypertension diseases that cause disorders of BP regulation

4 Dietary Na Kidneys Urinary Na Renin Blood volume Blood pressure Na transport Aldosterone ACTH GRA Adrenal hyperplasia Deoxycorticosterone MN receptor Cortisol Cortisone ENaC (Liddles) Gordons syndrome Adducin Angiotensinogen Progesterone sensitivity AME

5 Dietary Na Kidneys Urinary Na Renin Blood volume Blood pressure Na transport Aldosterone ACTH GRA Adrenal hyperplasia Deoxycorticosterone MN receptor Cortisol Cortisone ENaC (Liddles) Gordons syndrome Adducin Angiotensinogen Progesterone sensitivity AME

6 Glucocorticoid-remediable aldosteronism (GRA) AD monogenic HT Results from a chimeric gene product that place 18-hydroxylase (Aldosterone synthase) under control of ACTH promoter ACTH-regulated 18-hydroxylase activity is aberrantly expressed in Zona fasciculata and acts upon control to form 18-hydroxy cortisol and 18-oxocortisol

7 Aldosterone Adrenal hormones are synthesized in different areas of adrenal cortex –ZG…Aldosterone –ZF…Glucocorticoid (cortisol) –ZR…Androgen,estrogen ZG…well adapted for aldosterone production –low conc of 17-alpha hydroxylase –final step in conversion of corticosterone to aldosterone

8 Aldosterone Aldosterone synthase –>95% homology with 11-hydroxylase –convert deoxycortisol to cortisol in ZF –addition of hydroxyl group at C-18 –oxidation to an aldehyde Two distinct genes products perform terminal step in biosynthesis –11 beta-hydroxylase (CYP11B1)…glucocorticoid –18-hydroxylase or Aldosterone synthase (CYP11B2)…mineralocorticoid

9 Linkage analysis localized the gene to chromosome 8 Chimeric gene consisting of the promoter-regulatory region of CYP11B1 and structural portion of CYP11B2 is localized between CYP11B2 and CYP11B1 Protein product…perform all reaction required for aldosterone production >>>ACTH-dependent hyperaldosteronism Ectopic expression of chimeric protein express CYP17…formation of 18-hydroxy and 18-oxocortisol (biochemical hallmarks) Chimeric gene resulted from miotic mismatch and unequal crossing-over…located 5 to intron 4 of CYP11B gene

10 GRA ZF ZG A II ACTH Aldo Aldosterone Cortisol Aldo 18-OH Cortisol 18-OXO Cortisol ZG ZF Normal GRA

11 Clinical…volume expansion Salt-sensitive HT Tend to have hypokalemic metabolic alkalosis Low renin-High aldostertone 18-OH and 18-oxocortisol in plasma and urine Replacement of prednisolone ameliorate HT & disappearance of abnormal stetroids

12 GRA and Pregnancy GRA not appeared to more prone to pre- eclampsia GRA…chronic HT, increased risk of exacerbation of HT during pregnancy Cesarean section rate > general and other obstetrics…2 folds Wycoff JA et al. Hypertension, 2000

13 Apparent Mineralocorticoid Excess (AME) AR form of monogenic HT Results from inactivation of 11-beta-hydroxysteroid dehydrogenase type2 (11B-HSD2) Causing reduced metabolism of cortisol to cortisone…local cortisol excess and MN response Metabolic clearance of cortisol is prolonged in AME Excess urinary excretion of the reduced metabolites of cortisol… increased Tetrahydrocortisol:tetrahydrocortisone Ratio


15 Fredrick V. Osorio and Stuart L. Linus

16 AME Resembles the syndrome observed in persons integrity large amounts of licorice Volume expansion Salt-sensitive HT Hypokalemic metabolic alkalosis Low renin-Low aldosterone HT respond to thiazide or spironolactone but no aldosterone and abnormal steroid products in urine

17 AME Palermo et al. ( NEJM, 1998 ) –Resolution of AME syndrome after KT in 38 year old woman –Abnormal ratio of reduced metabolite of cortisol/cortisonr in urine was not corrected –Ratio of urinary free cortisol to cortisone was corrected and correlated with the resolution of the syndrome

18 Liddles syndrome AD form of monogenic HT Volume expansion Salt-sensitive HT Hypokalemic metabolic alkalosis Low renin-Low aldosterone Not respond to spironolactone But triamterene can reduce BP

19 Liddles Syndrome A 16 yr-old girl referred with a provisional diagnosis of primary aldosteronism BP was consistently elevated at 180/120 Serum K was 2.6 mEq/l and serum HCO mEq/l The pts younger brother had BP 200/110,serun K 2.4 mEq/l and serum HCO mEq/l

20 Liddles Syndrome Workup Initial observation Low rate of aldosterone secretion No response to SV-9055,an inhibitor of aldosterone secretion No response to spironolactone, a mineralocorticoid receptor antagonist Triamterene a direct inhibitor of CCD Na+ and K+ transport, normalizes BP and serum K+ Renal transplantation normalize BP and serum K+ (Botero-Velez et al,NEJM 1994)

21 ENaC MUTATIONS IN LIDDLES 5 kindreds with c-terminal deletions of amino acid in Beta-ENaC (Shimkets et al,cell,1994) 1 kindred with c-terminal of 76 amino acid in Gamma- ENaC 2 kindreds with missense mutation of Gamma-ENaC ( Hansson et al, Nature,1995) HYPERGENE data (Persu et al.Hypertension,1998) –Sequence analysis of Beta ENaC subunit in 532 HT proband (101 low renin HT) –Missense mutation in 7 unrelated individual,3 probands of African –Mutation …T594M -6%, G442V -34.8%

22 NEDD4 protein binds to PY domain >>> internalized and destroy PY domain mutation,NEDD4 cant bind,internalize and destroy

23 Regulation of ENaC Daniela Rotin CO-NH,2000

24 Fredrick V. Osorio and Stuart L. Linus

25 Gordons syndrome One or more gene responible for Type II pseudohypoaldosteronism Linkage analysis to chromosome 1q31-q42, 17p11-q21, 12p?

26 Type II pseudohypoaldosteronism in adults with HT( Gordons syndrome ) –HyperK, intact renal Na conservation –Normal renal function, HT, low PRA, low to normal PA –Normal antinatriuretic response to MN –But absent kaliuretic response –Distinguished from hyporenin/hypoaldosteronism by Normal renal function Absent Hx of DM, uniform presence of HT Absence of salt wasting when dietary NaCl restrict Lack of kaliuretic response to MN

27 Type II pseudohypoaldosteronism in adults with HT( Gordons syndrome ) –Schambelan et al….primary defect may be related to enhanced Cl reabsorption in early distal tubule… limit Na delivery to more distal tubule,decreased lumen negativity,impaired K secretion due to voltage-shunt effect –Increased NaCl reabsorption expand ECF volume…HT and suppress RAAS –Hyper K contributes to inhibition of renin secretion –PA..normal or suppressed depending upon balance between inhibitory effect of volume expansion and stimulatory effect of hyper K

28 Type II pseudohypoaldosteronism in adults with HT( Gordons syndrome ) –Rx with thiazides or loop diuretics …enhance renal H,K excretion…correct met acidosis, hyper K, HT, return PA&PRA to normal

29 Pseudohypoaldosteronism Type II pseudohypoaldosteronism in adults with HT( Gordons syndrome ) Na Cl shunt KHKH NaCl reabsorption Transtubular PD ECF expansion K/H secretion hyperK acidosis Hyporenin/hypoaldo

30 Mineralocorticoid Receptor Defect Geller et al. ( Science, 2000 ) New mendelian form of HT caused by an activating mutation in MR Screened MR coding regions in 75 individuals referred for evaluating monogenic HT One patient…15 year boy with severe HT(210/120 mmHg), normokalemia, suppressed aldosterone level…Heterozygous for missense mutation altering Serine at codon 810 (S810) to Leucine (L810) …MR L810

31 Progesterone activates MR L810 MR is a ligand-activated transcription factor Structures… –Long N terminal domain binds to transcription factors –Central DNA-binding domain –C terminal ligand-binding domain (LBD) L810 mutation in LBD altered receptor- ligand specificity

32 Progesterone activates MR L810 No difference between receptor in response to MR agonosts ( aldosterone, cortisol) But MR L810 proned to have significant activity in the absence of ligand Antagonists of wild-type MR (progesterone)…potent agonists of MR L810 Spironolactone… activated MR L810 …... contraindicated in MR L810

33 Pregnancy in MR L810 2 affected women and 5 pregnants Severe maternal HT, hypokalemia, hyperkaliuria Termination of pregnancy or early delivery No other signs of pre-eclampsia Support of in-vitro finding that progesterone agonized MR L810

34 Progesterone-induced Activation of MR L810 Require a novel helix3/helix5 interaction S810 on helix 5 was near alanine 773 (A773) on helix 3 but distance is too great for stabilizing effect When L810 is substituted, longer non-polar leucine side chain come into close contact with A773

35 Progesterone-induced Activation of MR L810 How does this interaction allow progesterone-mediated activation of MR? –Progesterone distinguished from MR agonists by absence of C-21 hydroxyl group –C-21 hydroxyl group form hydrogen bond with carbonyl group of asparagine 770 (N770) on helix 3…necessary for aldosterone-induced activation of MR –In MR L810 …novel interaction of A773 with L810 replace this function

36 Helix3/helix5 interaction in progesterone mediated activation of MR L810 Geller DS et al. Science,2000

37 Autosomal-dominant HT with brachydactyly First described bt Bilginturan et al. In 1973 Dramatic increase in BP with age and die of stoke before age 50 Map the gene to 12p PRA and aldosterone are normal Not salt-sensitive Normal RAAS and catecholamine response

38 Autosomal-dominant HT with brachydactyly Evidence of Neurovascular contact (NVC) –Left sided posterior cerebellar artery or ventricular artery loop or bilateral –May result in hyperactive dysfunction of underlying structures HT...may related to increased sympathetic activity

39 Thank You

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