Liddle Syndrome

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=== Genetic Basis  ===
 
=== Genetic Basis  ===
  
Liddle mutation is&nbsp;in the C terminus of&nbsp;the beta and gamma subunits, which play a key role in trafficking the [[ENaC protein|ENaC protein]]. The mutated region, called the PY motif (Pro-Pro-X-Tyr) is a binding site for Nedd4-2. The Nedd4-2 binds ENaC PY motif via its WW domain&nbsp;<ref>Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, Rotin D: WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. Embo J 1996 , 15(10):2371-2380</ref>. This normally leads to [[Ubiquitylation|ubiquitylation]] and [[Endocytosis|endocytosis]] reducing the number of [[Enac|ENaC]] in the [[Plasma membrane|plasma membrane]]&nbsp;<ref>Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D: Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. Embo J 1997 , 16(21):6325-6336</ref>. However in Liddle's Syndrome the [[Endocytosis|endocytosis is]] impaired due to the inability of the PY motif of ENaC to bind Nedd4-2, leading to retention of ENaC in the plasma membrane and elevated ENaC activity<ref>Abriel H, Loffing J, Rebhun JF, Pratt JH, Schild L, Horisberger JD, Rotin D, Staub O: Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome. J Clin Invest 1999 , 103(5):667-673</ref>. This increased ENaC activity increases Na+ (and fluid) absoption<ref>Garty H, Palmer LG: Epithelial sodium channels: function, structure, and regulation. Physiol Rev 1997 , 77(2):359-396</ref>,leading to increased blood volume and hypertension.<br>
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Liddle mutation is&nbsp;in the C terminus of&nbsp;the beta and gamma subunits, which play a key role in trafficking the [[ENaC protein|ENaC protein]]. The site of mutation is in either the SCNN1B or SCNN1G genes<ref>http://rarediseases.info.nih.gov/gard/7381/liddle-syndrome/resources/1</ref>.&nbsp;The mutated region, called the PY motif (Pro-Pro-X-Tyr) is a binding site for Nedd4-2. The Nedd4-2 binds ENaC PY motif via its WW domain&nbsp;<ref>Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, Rotin D: WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. Embo J 1996 , 15(10):2371-2380</ref>. This normally leads to [[Ubiquitylation|ubiquitylation]] and [[Endocytosis|endocytosis]] reducing the number of [[Enac|ENaC]] in the [[Plasma membrane|plasma membrane]]&nbsp;<ref>Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D: Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. Embo J 1997 , 16(21):6325-6336</ref>. However in Liddle's Syndrome the [[Endocytosis|endocytosis is]] impaired due to the inability of the PY motif of ENaC to bind Nedd4-2, leading to retention of ENaC in the plasma membrane and elevated ENaC activity<ref>Abriel H, Loffing J, Rebhun JF, Pratt JH, Schild L, Horisberger JD, Rotin D, Staub O: Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome. J Clin Invest 1999 , 103(5):667-673</ref>. This increased ENaC activity increases Na+ (and fluid) absoption<ref>Garty H, Palmer LG: Epithelial sodium channels: function, structure, and regulation. Physiol Rev 1997 , 77(2):359-396</ref>,leading to increased blood volume and severe hypertension.<br>
  
 
=== Treatment  ===
 
=== Treatment  ===

Revision as of 10:10, 22 October 2013

Liddle's syndrome is an autosomal dominant disease. It is recognised by early and severe hypertension. With irregualtion in blood pressure, testing for Liddle's syndrome involves the measurement of plasma renin, plasma aldersterone and blood electrolyte levels such as concentration of Na(sodium) and K(potassium). These would be found to be abnormally low in a patient with Liddle's syndrome.

Genetic Basis

Liddle mutation is in the C terminus of the beta and gamma subunits, which play a key role in trafficking the ENaC protein. The site of mutation is in either the SCNN1B or SCNN1G genes[1]. The mutated region, called the PY motif (Pro-Pro-X-Tyr) is a binding site for Nedd4-2. The Nedd4-2 binds ENaC PY motif via its WW domain [2]. This normally leads to ubiquitylation and endocytosis reducing the number of ENaC in the plasma membrane [3]. However in Liddle's Syndrome the endocytosis is impaired due to the inability of the PY motif of ENaC to bind Nedd4-2, leading to retention of ENaC in the plasma membrane and elevated ENaC activity[4]. This increased ENaC activity increases Na+ (and fluid) absoption[5],leading to increased blood volume and severe hypertension.

Treatment

Amiloride, a diuretic, is used in the treatment of Liddle's syndrome. It works by inhibition of ENaC and so inhibition of sodium reabsorption and so water without depleting potassium levels.

References

  1. http://rarediseases.info.nih.gov/gard/7381/liddle-syndrome/resources/1
  2. Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, Rotin D: WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. Embo J 1996 , 15(10):2371-2380
  3. Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D: Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. Embo J 1997 , 16(21):6325-6336
  4. Abriel H, Loffing J, Rebhun JF, Pratt JH, Schild L, Horisberger JD, Rotin D, Staub O: Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome. J Clin Invest 1999 , 103(5):667-673
  5. Garty H, Palmer LG: Epithelial sodium channels: function, structure, and regulation. Physiol Rev 1997 , 77(2):359-396
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