Tuesday, September 7, 2010

Genetic causes of hypertension

And now for some board review tidbits! Below are some genetic causes of hypertension attributable to specific gene mutations.

  1. Glucocorticoid-remediable hyperaldosteronism (GRE)- Autosomal dominant condition caused by uneven crossing over on chromosome 8. A chimeric protein is created in which the ACTH-controlled promoter for 11 beta hydroxylase is joined to the structural gene encoding aldosterone synthase. Aldosterone is overexpressed, leading to a hyporeninemic, salt-sensitive state of volume expansion. Hypokalemia and metabolic alkalosis may be present. Glucocorticoid administration suppresses ACTH and thus also aldosterone synthase production.
  2. Apparent mineralocorticoid excess (AME)- Autosomal recessive disorder characterized by deficiency in 11 beta hydroxysteroid dehydrogenase 2. 11 beta dehydrogenase 2 metabolizes cortisol to cortisone. In states of cortisol excess (here caused by decreased metabolism), cortisol binds to and activates type I mineralocorticoid receptors, causing an aldosterone-like effect. Hypokalemia, hypernatremia and hypertension are seen. Treatment is with dexamethasone, which suppresses endogenous cortisol production.
  3. Liddle’s syndrome- Autosomal dominant genetic mutation on chromosome 16 that causes defective ENaC ubiquitlyation and endocytosis, leading to increased ENaC cell surface expression and subsequent increased Na reabsorption. Presents in childhood with hypertension, hypokalemia and metabolic alkalosis. ENaC blockade with amiloride or triamterine plus a low Na diet are the usual treatment.
  4. Pseudohypoaldosteronism Type II (Gordon’s syndrome)-Not sure what the inheritance pattern is in this condition. A genetic defect in WNK kinases 1 or 4 causes a hyporeninemic, hypertensive state. The mechanism by which these WNK defects may cause high blood pressure is unclear, but the most common explanation is that the mutations lead to an increase in thiazide-sensitive Na-Cl transporter activity. WNK I inhibits ROMK in vitro, so it may cause decreased K secretion in vivo. WNKs may also increase paracellular Cl transport, which would decrease H and K secretion into the lumen. Treatment is with thiazides.
  5. Mineralocorticoid recepator activating mutation- please see the excellent post from June 7 from Mike on this condition, which was the answer to a board review question.


Tarun said...

Great concise review!-Tarun

Anonymous said...

Great review. Isn't Gordon's autosomal dominant?

Hakan Toka said...

Gordon syndrome is transmitted typically in autosomal-dominant fashion. WNK1 is on chromosome 12 and WNK4 is on chromosome 17. There is another locus on chromosome 1 with unknown gene.
Despite these two known genes there must be more disease genes causing this syndrome. There are several families which don't have any mutations in the known genes or don't map to the chromosome 1 locus.
There are several sporadic cases too which suggests either de novo mutations or recessive inheritance.