RESUMO
Aniridia is a panocular inherited rare eye disease linked to heterozygous mutations on the PAX6 gene, which fail to properly produce sufficient protein essential for normal eye development and function. Most of the patients suffer from aniridia-related keratopathy, a progressive opacification of the cornea. There is no effective treatment for this blinding disease. Here we screen for small compounds and identified Ritanserin, a serotonin 2A receptor antagonist, that can rescue PAX6 haploinsufficiency of mutant limbal cells, defective cell migration and PAX6-target gene expression. We further demonstrated that Ritanserin activates PAX6 production through the selective inactivation of the MEK/ERK signaling pathway. Our data strongly suggest that repurposing this therapeutic molecule could be effective in preventing or treating existing blindness by restoring corneal transparency.
Assuntos
Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Soluções Oftálmicas/farmacologia , Fator de Transcrição PAX6/genética , Ritanserina/farmacologia , Antagonistas da Serotonina/farmacologia , Células-Tronco/efeitos dos fármacos , Aniridia/tratamento farmacológico , Aniridia/genética , Aniridia/metabolismo , Aniridia/patologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , Epitélio Corneano/patologia , Regulação da Expressão Gênica , Células HEK293 , Haploinsuficiência , Humanos , Limbo da Córnea/efeitos dos fármacos , Limbo da Córnea/metabolismo , Limbo da Córnea/patologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Biológicos , Fator de Transcrição PAX6/agonistas , Fator de Transcrição PAX6/metabolismo , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/patologiaAssuntos
Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Brassica/química , Glucosinolatos/farmacologia , Imidoésteres/farmacologia , Animais , Aniridia/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Ataxia Cerebelar/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Deficiência Intelectual/tratamento farmacológico , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Oximas , SulfóxidosRESUMO
PURPOSE: To report the genetic basis for congenital glaucoma with clinical aniridia in an infant and a milder phenotype in her mother. METHODS: Prospective case series. RESULTS: An infant girl with almost complete lack of iris tissue was referred and treated for congenital glaucoma. Although the presumed clinical diagnosis was aniridia (On-line Mendelian Inheritance in Man [OMIM] AN2, # 106210), PAX6 sequencing was normal. Examination of the infant's mother was significant for Axenfeld-Rieger malformation (ARM): prominent Schwabe line, subtle iris hypoplasia, iris stands bridging the angle, increased intraocular pressure, and glaucomatous optic nerve cupping. Both parents and the infant underwent diagnostic FOXC1 DNA sequencing. A heterozygous M161K FOXC1 mutation was found in the infant and her mother but not in the father, who had a normal ocular examination. DISCUSSION: The spectrum of intrafamilial phenotypic variation associated with heterozygous FOXC1 mutation can be wide. FOXC1 mutation can be a cause of congenital glaucoma with clinical aniridia. Although such infants resemble the AN2 phenotype, the glaucoma of AN2 due to PAX6 mutation is typically secondary with onset several years after birth.