Somatic activating mutations in
| Autor: | Lara, Rodriguez-Laguna, Noelia, Agra, Kristina, Ibañez, Gloria, Oliva-Molina, Gema, Gordo, Noor, Khurana, Devon, Hominick, María, Beato, Isabel, Colmenero, Gonzalo, Herranz, Juan M, Torres Canizalez, Rebeca, Rodríguez Pena, Elena, Vallespín, Rubén, Martín-Arenas, Ángela, Del Pozo, Cristina, Villaverde, Ana, Bustamante, Carmen, Ayuso, Pablo, Lapunzina, Juan C, Lopez-Gutierrez, Michael T, Dellinger, Victor, Martinez-Glez |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Sirolimus Adolescent Class I Phosphatidylinositol 3-Kinases TOR Serine-Threonine Kinases Mutation Missense nutritional and metabolic diseases Article Lymphatic System Amino Acid Substitution Child Preschool Humans lipids (amino acids peptides and proteins) Female cardiovascular diseases Lymphangioleiomyomatosis Child Proto-Oncogene Proteins c-akt hormones hormone substitutes and hormone antagonists Research Articles Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). Here, Rodriguez-Laguna et al. report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of GLA. Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|