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Las mutaciones en kelch-like 3 y cullin 3 causan hipertensión y anomalías en los electrolitos
Lynn M Boyden1, Murim Choi, Keith A Choate
1Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Nature
|January 24, 2012
Resumen
Las mutaciones en los genes KLHL3 o CUL3 causan Pseudohypoaldosteronism tipo II (PHAII), un síndrome de hipertensión. Estos genes son cruciales para la presión arterial y el equilibrio de electrolitos, con las características de la enfermedad revertidas por los diuréticos tiazídicos.
Área de la Ciencia:
- Genética La genética.
- Nefrología Nefrología.
- Biología Molecular Biología Molecular
Sus antecedentes:
- La hipertensión es un importante factor de riesgo de enfermedad cardiovascular.
- El pseudohypoaldosteronismo tipo II (PHAII) es un síndrome genético raro que causa hipertensión, hipercalemia y acidosis metabólica.
- PHAII ofrece información sobre la sal renal y la homeostasis de electrolitos.
Objetivo del estudio:
- Para identificar las causas genéticas de la PHAII.
- Para aclarar los mecanismos fisiológicos subyacentes PHAII.II.
- Explorar el papel de KLHL3 y CUL3 en la regulación de la presión arterial.
Principales métodos:
- Se usó la secuenciación del exoma para identificar mutaciones en pacientes con PHAII.
- Análisis de las mutaciones genéticas KLHL3 y CUL3 y sus patrones de herencia.
- Investigó la función de KLHL3 y CUL3 en complejos de E3 ligasa.
- Examinó la expresión de KLHL3 y CUL3 en el riñón.
Principales resultados:
- Se identificaron mutaciones en KLHL3 o CUL3 en 41 familias de PHAII.
- Las mutaciones KLHL3 pueden ser recesivas o dominantes; las mutaciones CUL3 son dominantes y a menudo de novo.
- Tanto las mutaciones KLHL3 como las CUL3 interrumpen los procesos de ubiquitinación.
- Los síntomas de la enfermedad fueron mejorados por los diuréticos tiazídicos, implicando el cotransportador Na-Cl.
Conclusiones:
- KLHL3 y CUL3 son críticos para mantener la presión arterial, el potasio y la homeostasis del pH.
- Las mutaciones en KLHL3 y CUL3 causan PHAII a través de mecanismos que involucran la reabsorción renal de sal.
- La secuenciación del exoma es efectiva para identificar genes de enfermedades en trastornos genéticos complejos.
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