RESUMEN
Individuals with germline mutations in the gene encoding phosphatase and tensin homolog on chromosome ten (PTEN) are diagnosed with PTEN hamartoma tumor syndrome (PHTS) and are at high risk for developing breast, thyroid and other cancers and/or autoimmunity or neurodevelopmental issues including autism spectrum disorders. Although well recognized as a tumor suppressor, involvement of PTEN mutations in mediating such a diverse range of phenotypes indicates a more central involvement for PTEN in immunity than previously recognized. To address this, sequencing of the T-cell receptor variable-region ß-chain was performed on peripheral blood from PHTS patients. Based on patient findings, we performed mechanistic studies in two Pten knock-in murine models, distinct from each other in cell compartment-specific predominance of Pten. We found that PTEN mutations in humans and mice are associated with a skewed T- and B-cell gene repertoire, characterized by increased prevalence of high-frequency clones. Immunological characterization showed that Pten mutants have increased B-cell proliferation and a proclivity towards increased T-cell reactivity upon Toll-like-receptor stimulation. Furthermore, decreases in nuclear but not cytoplasmic Pten levels associated with a reduction in expression of the autoimmune regulator (Aire), a critical mediator of central immune tolerance. Mechanistically, we show that nuclear PTEN most likely regulates Aire expression via its emerging role in splicing regulation. We conclude that germline disruption of PTEN, both in human and mouse, results in compromised central immune tolerance processes that may significantly impact individual stress responses and therefore predisposition to autoimmunity and cancer.
Asunto(s)
Síndrome de Hamartoma Múltiple/genética , Fosfohidrolasa PTEN/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Factores de Transcripción/genética , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Proliferación Celular/genética , Modelos Animales de Enfermedad , Femenino , Técnicas de Sustitución del Gen , Mutación de Línea Germinal/genética , Síndrome de Hamartoma Múltiple/sangre , Síndrome de Hamartoma Múltiple/inmunología , Síndrome de Hamartoma Múltiple/patología , Humanos , Tolerancia Inmunológica/genética , Masculino , Ratones , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Proteína AIRERESUMEN
PURPOSE: Cowden syndrome results from germline mutations in the gene for phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and from variants in succinate dehydrogenase B and D subunits. We hypothesized that succinate accumulation may be common among individuals with SDH variants/mutations and those with PTEN mutations. METHODS: Urine and blood were collected from individuals meeting full or partial Cowden syndrome diagnostic criteria or those with paraganglioma (PGL) or a known susceptibility paraganglioma-associated gene mutation, and succinate was measured. PTEN, SDHB, SDHC, and SDHD genes were sequenced from genomic DNA. RESULTS: Elevated plasma succinate was observed in 13/21 (62%) individuals with germline PTEN, SDHB, or SDHD mutations as compared with 5/32 (16%) controls (P < 0.001), in 10/15 (67%) individuals with pathogenic PTEN mutations but in <20% of mutation-negative individuals meeting identical criteria, and in individuals with mutations in SDHB (1/1, 100%) and SDHD (2/5, 40%). CONCLUSION: Our data suggest that mutations in PTEN, SDHB, and SDHD reduce catalytic activity of succinate dehydrogenase, resulting in succinate accumulation, and identify a common biochemical alteration in these two patient populations (PTEN and SDHx mutation positive individuals). Plasma organic acid analysis may provide an effective and inexpensive screening method to determine when more expensive gene sequencing of PTEN and SDH genes is warranted.
Asunto(s)
Síndrome de Hamartoma Múltiple/sangre , Síndrome de Hamartoma Múltiple/genética , Fosfohidrolasa PTEN/genética , Succinato Deshidrogenasa/genética , Ácido Succínico/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ácidos Carboxílicos/sangre , Ácidos Carboxílicos/orina , Niño , Preescolar , Femenino , Estudios de Seguimiento , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/diagnóstico , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Paraganglioma/diagnóstico , Paraganglioma/genética , Análisis de Secuencia de ADN , Ácido Succínico/orinaAsunto(s)
Enfermedades de los Conductos Biliares/patología , Síndrome de Hamartoma Múltiple/patología , Anciano , Enfermedades de los Conductos Biliares/sangre , Conductos Biliares/patología , Biopsia con Aguja Fina , Proteína C-Reactiva/metabolismo , Pancreatocolangiografía por Resonancia Magnética , Femenino , Síndrome de Hamartoma Múltiple/sangre , Humanos , gamma-Glutamiltransferasa/sangreAsunto(s)
Sustitución de Aminoácidos , Globinas/genética , Hemoglobinas Anormales/aislamiento & purificación , Mutación Missense , Mutación Puntual , 2-Propanol/farmacología , Precipitación Química , Globinas/química , Síndrome de Hamartoma Múltiple/sangre , Síndrome de Hamartoma Múltiple/complicaciones , Hemoglobinas Anormales/química , Hemoglobinas Anormales/genética , Humanos , Masculino , Persona de Mediana Edad , Mapeo Peptídico , Desnaturalización Proteica , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
The PTEN/MMAC1, a putative tumor suppressor, has been demonstrated to dephosphorylate phosphatidylinositol 3, 4, 5-triphosphate, a key molecule involved in the insulin signaling pathway. The PTEN may act, therefore, as a negative regulator of insulin signaling. The patient with Cowden disease, having a heterozygous PTEN/MMAC1 gene mutation, a C to T substitution of a single base at codon 130, was suspected to have decreased amount of PTEN protein with phosphatase signature motif. We thought that the patient might be more sensitive to insulin than normal subjects. As expected, administration of a bolus of glucose resulted in a more rapid clearance of blood glucose than was observed in 5 control subjects, indicating the presence of insulin hypersensitivity in the patient. The euglycemic hyperinsulinemic clamp study provided additional evidence.
Asunto(s)
Glucemia/análisis , Genes Supresores de Tumor , Glucosa/farmacología , Síndrome de Hamartoma Múltiple/genética , Monoéster Fosfórico Hidrolasas/genética , Mutación Puntual , Proteínas Supresoras de Tumor , Adulto , Codón/genética , Glucosa/administración & dosificación , Prueba de Tolerancia a la Glucosa , Síndrome de Hamartoma Múltiple/sangre , Síndrome de Hamartoma Múltiple/enzimología , Humanos , Hiperinsulinismo/metabolismo , Insulina , Resistencia a la Insulina/genética , Masculino , Fosfohidrolasa PTEN , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolasas/química , Regiones Terminadoras GenéticasRESUMEN
A case of multiple hamartoma syndrome (Cowden's disease) associated with renal cell adenocarcinoma and primary neuroendocrine carcinoma of the skin is described. Neither of these neoplasms has been documented previously in association with this genodermatosis. A search for epidermal growth factor receptor (c-erb-B protooncogene) gene abnormalities in the kidney, liver, and thyroid, as well as in tissue of the primary neuroendocrine carcinoma, was negative. Serum obtained from the patient before his death contained elevated levels of both chromogranin A (2641 ng/mL; normal level, less than 20 ng/mL) and calcitonin (517 pg/mL; normal level, less than 200 pg/mL), suggesting that the patient's principal tumor was neuroendocrine in origin.