RESUMEN
The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.
Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil , Humanos , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Mutación/genética , ARN Mensajero/metabolismo , Expansión de Repetición de Trinucleótido/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/terapiaRESUMEN
Some 200 years ago, workers developed gingivitis, periodontal disease, alveolar crest bone sequestra, and draining fistulae after exposure to phosphorous fumes and phosphorous paste in the manufacture of the friction match. Many also suffered loss of teeth and pathologic fracture of the mandible. Known as "phossy jaw," the constellation rather abruptly vanished following the International Berne Convention of 1906. Today, "bis-phossy jaw" (bisphosphonate-induced osteonecrosis of the jaw) has surfaced with pathologic fractures and other features common to its predecessor, "phossy jaw." This modern equivalent is reported with ever-increasing frequency and is presented here in the format of a brief historical review and a case report that includes segmental en bloc extirpation of necrotic mandible and pain-free salvage. Computerized imagery and three-dimensional printing technology were successfully chosen to create and apply a custom titanium bone plate, without free-tissue transfer.
RESUMEN
The triplication of genes located on chromosome 21 is known to cause a wide spectrum of pathology seen in Down syndrome (DS), including leukemia, seizures, stroke, and mental retardation. Studies on RNA and protein expression of genes in DS brain have demonstrated the role of triplicated genes in several DS phenotypes. Significant changes in the expression of nontriplicated genes have also been observed. However, little information is available regarding the role of nonchromosome 21 genes in DS pathology. We have found that α-synuclein (SNCA), a presynaptic protein whose gene is located on chromosome 6 in the Ts65Dn mouse model for DS, is significantly reduced in the cortex and other brain regions. We hypothesize that this alteration may play a critical role in the reduced synaptic function observed in DS. We have found an increase in the level of neurosin, a key negative regulator of SNCA in Ts65Dn cortex. We have also found increased levels of protein phosphatase 2A, a negative regulator of the activation of tyrosine hydroxylase and a key enzyme in the biosynthetic pathway for dopamine in Ts65Dn cortex. These findings reveal potential target sites for intervention in the treatment of DS pathology.
Asunto(s)
Encéfalo/metabolismo , Síndrome de Down/metabolismo , Calicreínas/metabolismo , Transmisión Sináptica/fisiología , alfa-Sinucleína/biosíntesis , Adolescente , Adulto , Anciano , Animales , Western Blotting , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Humanos , Inmunohistoquímica , Ratones , Persona de Mediana Edad , Proteína Fosfatasa 2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
la principal causa hereditaria del retardo mental es el síndrome de Martin bell o del cromosoma X frágil,cuyos aspectos moleculares han sido recientemente reconocidos.Debido a la existencia de falsos(+)(-)en las técnicas de estudios convencionales(citogenéticas)nuevas metodologías se han implementado en forma rutinaria.Las mismas permiten el diagnóstico de certeza en los varones afectados,las mujeres portadoras y los varones trasmisores asintomáticos.Se reportan los hallazgos en cuatro pacientes(dos mujeres y dos varones)quienes habían sido catalogados como portadores de un sitio frágil en el cromosoma X y en quienes los estudios moleculares determinaron que sólo en dos de ellos esta patología estaba realmente presente.Estos resultados ponen en evidencia la necesidad de corroborar los hallazgos citogenéticos mediante esta metodología a efectos de proveer a la familia del asesoramiento genético correcto
