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Monogenic Hypertension
Thitisak Kitthaweesin MD.
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.
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
Angiotensinogen
ACTH
Adducin
Renin
Blood volume
Blood pressure
Dietary Na
GRA
Aldosterone
Adrenal
hyperplasia
Na transport
Kidneys
Deoxycorticosterone
MN receptor
ENaC
(Liddle’s)
Cortisol
Gordon’s Urinary Na
syndrome
Cortisone
Progesterone
sensitivity
AME
Angiotensinogen
ACTH
Adducin
Renin
Blood volume
Blood pressure
Dietary Na
GRA
Aldosterone
Adrenal
hyperplasia
Na transport
Kidneys
Deoxycorticosterone
MN receptor
ENaC
(Liddle’s)
Cortisol
Gordon’s Urinary Na
syndrome
Cortisone
Progesterone
sensitivity
AME
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
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
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
• 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
GRA
Normal
A II
ACTH
GRA
Aldo
ZG
ZF
A II
ACTH
Cortisol
Aldosterone
ZG
ZF
Cortisol
Aldo
18-OH Cortisol
18-OXO Cortisol
GRA
• 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
GRA and Pregnancy
• GRA not appeared to more prone to preeclampsia
• 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
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
Fredrick V. Osorio and Stuart L. Linus
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
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
Liddle’s syndrome
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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
Liddle’s 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 HCO330 mEq/l
• The pt’s younger brother had BP
200/110,serun K 2.4 mEq/l and serum
HCO3- 29 mEq/l
Liddle’s 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)
ENaC MUTATIONS IN LIDDLE’S
• 5 kindreds with c-terminal deletions of 45-75 amino acid
in Beta-ENaC (Shimkets et al,cell,1994)
• 1 kindred with c-terminal of 76 amino acid in GammaENaC
• 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%
NEDD4 protein binds to PY domain
>>> internalized and destroy
PY domain mutation,NEDD4 can’t
bind,internalize and destroy
Regulation of ENaC
Daniela Rotin CO-NH,2000
Fredrick V. Osorio and Stuart L. Linus
Gordon’s syndrome
• One or more gene responible for Type
II pseudohypoaldosteronism
• Linkage analysis to chromosome
1q31-q42, 17p11-q21, 12p?
• Type II pseudohypoaldosteronism in adults with
HT( Gordon’s 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
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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
• Type II pseudohypoaldosteronism in adults with
HT( Gordon’s 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
• Type II pseudohypoaldosteronism in adults
with HT( Gordon’s syndrome )
– Rx with thiazides or loop diuretics …enhance
renal H,K excretion…correct met acidosis,
hyper K, HT, return PA&PRA to normal
Pseudohypoaldosteronism
• Type II pseudohypoaldosteronism in adults
with HT( Gordon’s syndrome )
NaCl reabsorption
Na
Cl shunt
ECF expansion
Hyporenin/hypoaldo
K
H
hyperK
Transtubular PD
K/H secretion
acidosis
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) …MRL810
Progesterone activates MRL810
• 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 receptorligand specificity
Progesterone activates MRL810
• No difference between receptor in response
to MR agonosts ( aldosterone, cortisol)
• But MRL810 proned to have significant
activity in the absence of ligand
• Antagonists of wild-type MR
(progesterone)…potent agonists of MRL810
• Spironolactone… activated MRL810
…...contraindicated in MRL810
Pregnancy in MRL810
• 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 MRL810
Progesterone-induced Activation of MRL810
• 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
Progesterone-induced Activation of MRL810
• 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 MRL810 …novel interaction of A773 with L810
replace this function
Helix3/helix5 interaction in progesterone mediated
activation of MRL810
Geller DS et al. Science,2000
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
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
Thank You