RESUMEN
Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects - usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2.
Asunto(s)
Exostosis Múltiple Hereditaria/genética , Mutación , N-Acetilglucosaminiltransferasas/genética , Población Blanca/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Femenino , Alemania , Humanos , Masculino , Datos de Secuencia Molecular , Empalme del ARN , Adulto JovenRESUMEN
BACKGROUND: Peutz-Jeghers syndrome (PJS), a rare hereditary disorder, is characterized by the occurrence of gastrointestinal hamartomatous polyps associated with mucocutaneous pigmentation. Patients are at an increased cancer risk not only for gastrointestinal but also for extraintestinal neoplasms. PATIENTS AND RESULTS: We report on the clinical and molecular findings in 3 young female patients with PJS; 2 of them suffered from severe gynecological cancer. One patient died at the age of 29 years of an incurable mucin-producing cervical adenocarcinoma. Another patient had a papillary serous carcinoma of the ovary. In all patients, we identified corresponding mutations in the STK11 gene, 2 of them novel. CONCLUSION: PJS should be considered in differential diagnosis in young women with gynecological malignancies. Identification of STK11 mutations in patients and their relatives can help to improve the clinical management.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de los Genitales Femeninos/diagnóstico , Neoplasias de los Genitales Femeninos/genética , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Adulto , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Mutación/genética , Proteínas de Neoplasias/genética , FenotipoRESUMEN
Mowat-Wilson syndrome (MWS) is a rare mental retardation-multiple congenital anomalies syndrome associated with typical facial dysmorphism. Patients can show a variety of other anomalies like short stature, microcephaly, Hirschsprung disease, malformations of the brain, seizures, congenital heart defects and urogenital anomalies. Mutations leading to haploinsufficiency of the ZFHX1B gene have been described as the underlying cause of this condition. We report on the clinical findings in a 2(1/2)-year-old boy with some aspects out of the MWS-spectrum in addition to unusual anomalies and a novel missense mutation in the ZFHX1B gene.