RESUMO
Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.
Assuntos
Proteínas de Ciclo Celular , Microcefalia , Humanos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Microcefalia/genética , Reparo do DNA/genética , Cromossomos/metabolismo , Instabilidade Genômica , Proteínas de Ligação a DNA/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Cromossômicas não Histona/metabolismoRESUMO
BACKGROUND: Transoral laser microsurgery is successfully performed in the treatment of primary laryngeal carcinomas. Few publications deal with the application in patients with recurrent glottic carcinomas after radiation failure. Our study aims to review our experience with transoral laser microsurgery in these patients. METHODS: Thirty-four patients with early and advanced recurrent glottic carcinoma after full-course radiotherapy (rT1, n = 11; rT2, n = 10; rT3, n = 10; rT4, n = 3) had CO(2) laser treatment with curative intent between 1987 and 1998. RESULTS: Twenty-four patients (71%) were cured with one or more laser procedures. In nine patients, recurrences could not be controlled by laser microsurgery: six patients underwent total laryngectomy and three palliative treatment. One patient received total laryngectomy because of chondronecrosis after laser treatment. With a median follow-up interval of 38.6 months, the 3-year and 5-year disease-specific survival was 86%. The overall 3-year survival rate was 74%; the corresponding 5-year survival rate was 53%. No major complications occurred. In three cases, temporary tracheostomy was needed. CONCLUSIONS: In early-stage and advanced-stage recurrent glottic carcinomas after radiotherapy, CO(2) laser treatment can successfully be used as a curative organ-preserving procedure. Compared with salvage laryngectomy, results are superior with respect to preservation of laryngeal function. Great expertise is required, especially in resections of advanced-stage recurrent carcinomas.
