RESUMEN
We have identified a novel germline mutation in the PTEN tumour suppressor gene. The mutation was identified in a patient with a glioma, and turned out to be a heterozygous germline mutation of PTEN (Arg234Gln), without loss of heterozygosity in tumour DNA. The biological consequences of this germline mutation were investigated by means of transfection studies of the mutant PTEN molecule compared to wild-type PTEN. In contrast to the wild-type molecule, the mutant PTEN protein is not capable of inducing apoptosis, induces increased cell proliferation and leads to high constitutive PKB/Akt activation, which cannot be increased anymore by stimulation with insulin. The reported patient, in addition to glioma, had suffered from benign meningioma in the past but did not show any clinical signs of Cowden disease or other hereditary diseases typically associated with PTEN germline mutations. The functional consequences of the mutation in transfection studies are consistent with high proliferative activity. Together, these findings suggest that the Arg234Gln missense mutation in PTEN has oncogenic properties and predisposes to brain tumours of multiple lineages.
Asunto(s)
Sustitución de Aminoácidos , Neoplasias Encefálicas/genética , Lóbulo Frontal , Mutación de Línea Germinal , Neoplasias Meníngeas/genética , Meningioma/genética , Mutación Missense , Proteínas de Neoplasias/genética , Neoplasias Primarias Múltiples/genética , Oligodendroglioma/genética , Monoéster Fosfórico Hidrolasas/genética , Mutación Puntual , Proteínas Serina-Treonina Quinasas , Proteínas Supresoras de Tumor/genética , Adulto , Apoptosis/genética , Neoplasias Encefálicas/patología , División Celular , Linaje de la Célula , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Activación Enzimática/efectos de los fármacos , Lóbulo Frontal/patología , Predisposición Genética a la Enfermedad , Humanos , Insulina/farmacología , Pérdida de Heterocigocidad , Masculino , Neoplasias Meníngeas/patología , Meningioma/patología , Modelos Moleculares , Proteínas de Neoplasias/química , Proteínas de Neoplasias/fisiología , Neoplasias Primarias Múltiples/patología , Oligodendroglioma/patología , Fosfohidrolasa PTEN , Monoéster Fosfórico Hidrolasas/química , Monoéster Fosfórico Hidrolasas/fisiología , Conformación Proteica , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Transfección , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/fisiología , Células U937/efectos de los fármacos , Células U937/enzimologíaRESUMEN
BACKGROUND: Multiple endocrine neoplasia type 2A (MEN 2A) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Familial MTC (FMTC) is characterized by MTC only. Both MEN 2A and FMTC are caused by germline mutations of the RET proto-oncogene. PURPOSE: To assess genotype/phenotype correlations, large families have to be examined periodically over a long period using an extensive screening program. PATIENTS AND METHODS: Since 1973, we screened a large family with hereditary C cell carcinoma for MTC, pheochromocytoma, and parathyroid disease by clinical tests and imaging methods. A germline codon Cys618 to Ser mutation in the RET proto-oncogene was recently identified in this family. The disease phenotype associated with this mutation was compared with that of Cys634 mutations in some other large MEN 2A families. RESULTS: The distinct course of disease in the family described here is similar to that in other FMTC families and MEN 2A families with a Cys618 mutation of the RET gene, but clearly different from that in families with a Cys634 mutation. The frequency of pheochromocytomas and parathyroid disease is clearly lower, whereas cure rates and life expectancy are higher. However, in families with a Cys618 mutation, pheochromocytoma and parathyroid disease do occur. CONCLUSION: In FMTC families with cysteine codon mutations of the RET proto-oncogene, screening for other endocrinopathies is mandatory, since these may not be MTC-only families. Therefore, we suggest that MEN 2A families should not be subclassified into MEN 2A and FMTC, but rather according to their specific mutation in the RET protein (i.e., for this family MEN 2A RET C618S).
Asunto(s)
Carcinoma Medular/genética , Cisteína/genética , Proteínas de Drosophila , Mutación de Línea Germinal , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Neoplasias de la Tiroides/genética , Neoplasias de las Glándulas Suprarrenales/genética , Adulto , Anciano , Carcinoma Medular/patología , Sondas de ADN , Femenino , Genotipo , Humanos , Hiperparatiroidismo/genética , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/genética , Linaje , Fenotipo , Feocromocitoma/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-ret , Neoplasias de la Tiroides/patologíaRESUMEN
The incidence of human fetal breathing movements was studied in normal pregnancies before and after administration of 50 g glucose or a placebo (water) at 24 and 28 weeks. Glucose or water was given to the same women on two separate days in a randomised order. No significant differences were present among the results on the placebo-day and the control period of the glucose-day at either gestational age. On the glucose-day, the incidence rose significantly from 3.6 to a maximum of 11.6% at 24 weeks, and from 6.7 to 30.2% at 28 weeks. At both ages the maximum was found 90-120 min after the intake of glucose. It is concluded that already at 24 weeks gestation the human fetus reacts with an increase of fetal breathing movements after the administration of glucose to the mother.
