RESUMEN
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.
Asunto(s)
Estudios de Asociación Genética , Enfermedad de Hirschsprung/genética , Proteínas de Homeodominio/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Proteínas Represoras/genética , Adolescente , Adulto , Alelos , Línea Celular , Niño , Preescolar , Codón sin Sentido , Facies , Femenino , Mutación del Sistema de Lectura , Expresión Génica , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/epidemiología , Proteínas de Homeodominio/metabolismo , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Japón , Masculino , Microcefalia/diagnóstico , Microcefalia/epidemiología , Fenotipo , Prevalencia , Estabilidad Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/metabolismo , Adulto Joven , Caja Homeótica 2 de Unión a E-Box con Dedos de ZincRESUMEN
Array using 2,173 BAC clones covering the whole human genome has been constructed. All clones spotted were confirmed to show a unique signal at the predicted chromosomal location by FISH analysis in our laboratory. A total of 30 individuals with idiopathic mental retardation (MR) were analyzed by comparative genomic hybridization using this array. Three deletions, one duplication, and one unbalanced translocation could be detected in five patients, which are likely to contribute to MR. The constructed array was shown to be an efficient tool for the detection of pathogenic genomic rearrangements in MR patients as well as copy number polymorphisms (CPNs).
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Artificiales Bacterianos/genética , Genoma Humano , Discapacidad Intelectual/genética , Hibridación de Ácido Nucleico/métodos , Bandeo Cromosómico , Deleción Cromosómica , Femenino , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/etiología , Cariotipificación , Masculino , Translocación GenéticaRESUMEN
Patients with 9q34.3 terminal deletion usually show a clinically recognizable phenotype characterized by specific facial features (microcephaly, flat face, arched eyebrows, hypertelorism, short nose, anteverted nostrils, carp mouth and protruding tongue) in combination with severe mental retardation, hypotonia, and other anomalies. We analyzed six unrelated patients with a various 9q34.3 terminal deletion. While having different-sized 9q34.3 deletions, all of these patients shared several distinctive anomalies. These anomalies are likely to arise from a commonly deleted region at distal 9q34.3. Fluorescence in situ hybridization (FISH) analysis using a dozen BAC clones mapped at the 9q34.13-q34.3 region defined the shortest region of deletion overlap (SRO) as a 1-Mb segment proximal to 9qter containing eight known genes. Possible candidate genes delineating specific phenotypes of the 9q34.3 terminal deletion syndrome are discussed.
Asunto(s)
Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 9/genética , Discapacidad Intelectual/genética , Centrómero/genética , Trastornos de los Cromosomas/diagnóstico , Cromosomas Artificiales Bacterianos/genética , Femenino , Haplotipos , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/diagnóstico , Masculino , Síndrome , Telómero/genéticaRESUMEN
We described three unrelated children with cryptic 9q34.3 rearrangements and similar clinical manifestations: two with 9q34.3 terminal deletions and the other with an unbalanced translocation involving 9q34.3-qter monosomy and 6p25-pter trisomy. Common features among the three we studied and the other six patients with 9q34.3 deletions in the literature include microcephaly, mental retardation (MR), hypotonic, and epileptic seizures. Their facial characteristics included flat face, arched eyebrows, synophrys, hypertelorism, short nose, anteverted nostrils, carp mouth, protruding tongue, micrognathia, and pointed chin. Other frequent abnormalities were cardiac abnormalities, cryptorchidism or hypospadias, and abnormal toes. These findings are characteristic enough to be a clinically recognizable syndrome.