RESUMEN
BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease associated with contraction of arrays of tandem 3.3-kb units (D4Z4) on subtelomeric 4q. Disease-linked arrays usually have fewer than 11 repeat units. Equally short D4Z4 arrays at subtelomeric 10q are not linked to FSHD. The newly described 4qA161 haplotype, which is more prevalent in pathogenic 4q alleles, involves sequences in and near D4Z4. METHODS: We developed two new assays for 4qA161, which are based upon direct sequencing of PCR products or detecting restriction fragment length polymorphisms. They were used to analyse single nucleotide polymorphisms (SNPs) indicative of 4q161 alleles. RESULTS: All (35/35) FSHD patients had one or two 4qA161 alleles (60% or 40%, respectively). In contrast, 46% (21/46) of control individuals had no 4qA161 allele (p<10(-4)), and 26% had homozygous 4qB163 alleles. CONCLUSIONS: Our results from a heterogeneous population are consistent with the previously described association of the 4qA161 haplotype with FSHD, but a causal association with pathogenesis is uncertain. In addition, we found that haplotype analysis is complicated by the presence of minor 10q alleles. Nonetheless, our sequencing assay for the 4qA161allele can enhance molecular diagnosis of FSHD, including prenatal diagnosis, and is simpler to perform than the previously described assay.
Asunto(s)
Cromosomas Humanos Par 4/genética , Haplotipos/genética , Distrofia Muscular Facioescapulohumeral/genética , Telómero/genética , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Distrofia Muscular Facioescapulohumeral/diagnóstico , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/métodos , Homología de Secuencia de Ácido Nucleico , Secuencias Repetidas en Tándem/genéticaRESUMEN
Human papillomaviruses (HPVs) are a causative factor in over 90% of cervical and 25% of head and neck squamous cell carcinomas (HNSCCs). The C terminus of the high-risk HPV 16 E6 oncoprotein physically associates with and degrades a non-receptor protein tyrosine phosphatase (PTPN13), and PTPN13 loss synergizes with H-Ras(V12) or ErbB2 for invasive growth in vivo. Oral keratinocytes that have lost PTPN13 and express H-Ras(V12) or ErbB2 show enhanced Ras/RAF/MEK/Erk signaling. In co-transfection studies, wild-type PTPN13 inhibited Ras/RAF/MEK/Erk signaling in HEK 293 cells that overexpress ErbB2, EGFR or H-Ras(V12), whereas an enzymatically inactive PTPN13 did not. Twenty percent of HPV-negative HNSCCs had PTPN13 phosphatase mutations that did not inhibit Ras/RAF/MEK/Erk signaling. Inhibition of Ras/RAF/MEK/Erk signaling using MEK inhibitor U0126 blocked anchorage-independent growth in cells lacking PTPN13. These findings show that PTPN13 phosphatase activity has a physiologically significant role in regulating MAP kinase signaling.
Asunto(s)
Carcinoma de Células Escamosas/enzimología , Sistema de Señalización de MAP Quinasas , Infecciones por Papillomavirus/enzimología , Proteína Tirosina Fosfatasa no Receptora Tipo 13/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 13/metabolismo , Receptor ErbB-2/genética , Animales , Butadienos/farmacología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Papillomavirus Humano 16 , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Ratones Endogámicos C57BL , Nitrilos/farmacología , Proteínas Oncogénicas Virales , Infecciones por Papillomavirus/patología , Fosforilación , Proteína Tirosina Fosfatasa no Receptora Tipo 13/deficiencia , Receptor ErbB-2/metabolismo , Proteínas RepresorasRESUMEN
A 62-year-old male with a history of Wegener's granulomatosis and immunosuppressive therapy presented with chronic olecranon bursitis. A black velvety mould with brown septate hyphae and tapered annellides was isolated from a left elbow bursa aspirate and was identified as an Exophiala species. Internal transcribed sequence rRNA sequencing showed the isolate to be identical to Exophiala oligosperma. The patient was successfully treated with aspiration and intrabursal amphotericin B.