RESUMEN
BACKGROUND: Germline mutations in the phosphatase PTEN are associated with diverse human pathologies, including tumour susceptibility, developmental abnormalities and autism, but any genotype-phenotype relationships are poorly understood. METHODS: We have studied the functional consequences of seven PTEN mutations identified in patients diagnosed with autism and macrocephaly and five mutations from severe tumour bearing sufferers of PTEN hamartoma tumour syndrome (PHTS). RESULTS: All seven autism-associated PTEN mutants investigated retained the ability to suppress cellular AKT signalling, although five were highly unstable. Observed effects on AKT also correlated with the ability to suppress soma size and the length and density of dendritic spines in primary neurons. Conversely, all five PTEN mutations from severe cases of PHTS appeared to directly and strongly disrupt the ability to inhibit AKT signalling. CONCLUSIONS: Our work implies that alleles causing incomplete loss of PTEN function are more commonly linked to autism than to severe PHTS cases.
Asunto(s)
Trastorno Autístico/genética , Predisposición Genética a la Enfermedad , Síndrome de Hamartoma Múltiple/genética , Patrón de Herencia/genética , Mutación Missense/genética , Fosfohidrolasa PTEN/genética , Trastorno Autístico/enzimología , Biocatálisis , Células Cultivadas , Síndrome de Hamartoma Múltiple/enzimología , Humanos , Neuronas/metabolismo , Fosfohidrolasa PTEN/química , Estabilidad ProteicaRESUMEN
Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology and establishing the correct diagnosis can be challenging. Although dysfunction of the anterior visual pathways is uncommon, it is the most common neuro-ophthalmological manifestation of this condition and given the potential for irreversible, severe visual loss, prompt diagnosis and treatment are essential. We describe a patient with optic perineuritis as a rare initial presentation of sarcoidosis and discuss the underlying pathophysiology and management.