Expression constructs are subject to position‐effects in transgenic assays unless they harbour elements that protect them from negative or positive influences exerted by chromatin at the site of ...integration. Locus control regions (LCRs) and boundary elements are able to protect from position effects by preventing heterochromatization of linked genes. The LCR in the human β‐globin gene locus is located far upstream of the genes and composed of several erythroid specific DNase I hypersensitive (HS) sites. Previous studies demonstrated that the LCR HS sites act synergistically to confer position‐independent and high‐level globin gene expression at different integration sites in transgenic mice. Here we show that LCR HS sites 2 and 3, in combination with boundary elements derived from the chicken β‐globin gene locus, confer high‐level human β‐globin gene expression in different chromosomal integration sites in transgenic mice. Moreover, we found that the construct is accessible to nucleases and highly expressed when integrated in a centromeric region. These results demonstrate that the combination of enhancer, chromatin opening and boundary activities can establish independent expression units when integrated into chromatin.
We report on a 34-year-old developmentally disabled man referred to our clinic for evaluation of possible Prader-Willi syndrome on the basis of obesity and voracious appetite. Cytogenetic and ...molecular analysis revealed a 47, XYY karyotype and the presence of a trinucleotide repeat expansion resulting in fragile X syndrome. To our knowledge, this is the first report of concurrence of XYY and fragile X syndrome in the medical literature. Review of sex chromosome abnormalities associated with fragile X syndrome and phenotypic considerations are presented.
The extent to which autoimmunity contributes to thyroid dysfunction in Down Syndrome (DS) individuals has not been clarified. We studied 61 persons (34 males and 27 females) with DS (age 5 months to ...48 years) for the presence of thyroid autoantibodies (thyroid microsomal antibodies and thyroglobulin antibodies), pancreatic islet cell autoantibodies, gastric parietal cell autoantibodies, and adrenocortical autoantibodies. Thyroid function was determined by measurement of TSH. HLA-A, B and -DR typing was performed on 52 subjects. Forty of 61 subjects (66%) had thyroid dysfunction: elevated TSH values (greater than 5 mcIU/ml) were found in 35 of 61 individuals; 3 subjects had previously documented Hashimoto thyroiditis and were on therapy for hyperthyroidism; and 2 persons had Graves disease. No age or sex variation was detected. Seventeen (28%) subjects had thyroid autoantibodies. Fifteen of the 17 had thyroid dysfunction. Twelve of 25 subjects (48%) over 10 years with thyroid dysfunction had thyroid autoantibodies compared to only 3 of 15 (20%) under the age of 10 years. However, children less than of 10 years tended to have higher TSH values. Only 1 individual who had thyroid antibodies had gastric parietal cell autoantibodies present. Islet cell and adrenocortical autoantibodies were not found in any individuals. Neither thyroid dysfunction nor thyroid autoantibodies correlated with any HLA allele. These findings suggest that thyroid dysfunction in individuals with DS of all ages is a common heterogeneous disorder which cannot be solely explained on the basis of autoimmunity. We recommend that thyroid function be followed closely whether or not thyroid autoantibodies are present.
We report on an infant with preaxial acrofacial dysostosis (Nager syndrome) who was diagnosed prenatally as having an apparently balanced X/autosome translocation 46,X,t(X;9)(p22.1;q32)mat inherited ...from a previously diagnosed mosaic translocation carrier mother 46,XX/46,X,t(X;9)(p22.1;q32). Replication studies on amniocytes showed the normal X chromosome to be late replicating while the same studies repeated on the infant's lymphocytes showed the translocated X chromosome to be late replicating in most cells. Late replication studies of the mother's lymphocytes demonstrated that the normal X chromosome was late replicating in most cells. The presence of Nager syndrome in this infant may be the result of critical breakpoints and/or position effects on chromosome 9, inducing expression of a gene responsible for the syndrome.
Deficiency of methylenetetrahydrofolate reductase (MTHFR) is associated with a variable phenotype that includes mental retardation, gait abnormalities, and seizures. Many of the same clinical ...findings are also seen in patients with Angelman syndrome. We report on a patient with MTHFR deficiency who was initially diagnosed as having Angelman syndrome. This case illustrates that MTHFR deficiency can mimic the phenotype of Angelman syndrome and that MTHFR deficiency should be excluded in patients with manifestations of Angelman syndrome whose molecular studies of chromosome 15 are normal.
Arthrogryposis is a heterogeneous birth defect characterized by limitation of movement at multiple joints. One in 3,000 infants is born with arthrogryposis, and at least a third of these cases have a ...genetic cause. Four distinct types of X-linked arthrogryposis have been reported, and a severe lethal form recently was mapped to Xpll.3-qll.2. We now report an extended family affected with a novel variant of X-linked arthrogryposis that involves only the lower limbs. Linkage analysis with polymorphic DNA markers maps the disease locus in this unique family to the long arm of the human X chromosome between DXS1220 and DXS1205 in Xq23-27.
Velo-cardio-facial syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect are all associated with hemizygosity of ...22q11. While the prevalence of the deletions in these phenotypes has been studied, the frequency of deletions in patients presenting with velopharyngeal insufficiency (VPI) is unknown. We performed fluorescence in situ hybridization for locus D22S75 within the 22q11 region on 23 patients with VPI (age range 5-42 years) followed in the Craniofacial Clinic at the University of Florida. The VPI occurred either as a condition of unknown cause (n=16) or as a condition remaining following primary cleft palate surgery (n=7). Six of sixteen patients with VPI of unknown cause and one of seven with VPI following surgery had a deletion in the region. This study documents a high frequency of 22q11 deletions in those presenting with VPI unrelated to overt cleft palate surgery and suggests that deletion testing should be considered in patients with VPI.
Twenty-five cases of congenital rubella syndrome were recorded in 1,458,126 live births in 19 EUROCAT birth defects registries from 1980 to 1986. During the study period, the incidence declined ...steadily from 3.50 to 0.41 per 100,000 births. Rubella infection occurred in 12 multiparous women indicating failure in immunization programme.
PDF
