1/4. Birth of healthy female twins after preimplantation genetic diagnosis of cystic fibrosis combined with gender determination.Two healthy sisters with a familial history of mental retardation were referred to our centre for preimplantation genetic diagnosis (PGD). Their two brothers showed severe mental retardation. The molecular basis for their disorder could not be identified, but one of the sisters and the mother presented a highly skewed pattern of X-inactivation reinforcing the likelihood of an X-linked mode of inheritance. Both sisters requested PGD to avoid the abortion of potentially affected male fetuses. PGD for sex by fluorescent in-situ hybridization was carried out for the first sister and resulted in the birth of a female child. The second sister and her partner, whose niece had cystic fibrosis (CF), were tested for CF mutations, and were both found to be deltaF508 heterozygous. We developed an efficient single cell PCR protocol for the simultaneous amplification of the CF (deltadeltaF508) locus as well as the X-linked amelogenin gene and its highly homologous pseudogene on the y chromosome. Two PGD cycles were carried out to screen against male and deltaF508 homozygous deleted embryos. In each case several embryos could be selected for transfer and the second cycle resulted in a twin pregnancy followed by the birth of two healthy female infants.- - - - - - - - - - ranking = 1keywords = cell (Clic here for more details about this article) |
2/4. The proportion of cells with functional X disomy is associated with the severity of mental retardation in mosaic ring X turner syndrome females.turner syndrome females (45,X) do not have mental retardation (MR), whereas some mosaic ring X turner syndrome females, with 45,X/46,X,r(X), have severe MR. The MR is believed to be caused by a failure of x chromosome inactivation (XCI) of the small ring X chromosome, which leads to functional X disomy (FXD), To explore this hypothesis, we examined the proportion of FXD cells in the peripheral blood of four ring X turner syndrome females with various levels of MR, using two newly developed XCI assays based on dna methylation of X-linked genes. As a result, the two patients with extremely severe MR showed complete FXD patterns, whereas the remaining two patients with relatively milder MR showed partial FXD patterns. These results indicate that the proportion of FXD cells may be associated with the severity of MR in mosaic ring X turner syndrome females, although this association should be confirmed by examining brain cells during development. One of the cases with severe MR and a complete FXD pattern neither lacked the XIST gene nor had uniparental X isodisomy, and we discuss the mechanism of the failure of XCI in this case.- - - - - - - - - - ranking = 7keywords = cell (Clic here for more details about this article) |
3/4. Extended clinical phenotype, endocrine investigations and functional studies of a loss-of-function mutation A150V in the thyroid hormone specific transporter MCT8.OBJECTIVE: thyroid hormones, besides having other functions, are known to be essential for the development of the human brain. Recently the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter which is expressed in different regions of the human brain. Here we describe in detail the clinical and biochemical features in response to thyroid hormone administration of a boy carrying an MCT8 mutation (A150V) in the second transmembrane domain. methods: To study the functional impact of the mutation we performed triiodothyronine (T3) uptake, immunofluorescence and dimerization studies. RESULTS: Thyroid hormone (l-thyroxine (LT4) and LT3) administration did not result in any significant clinical changes; however, with high doses of LT4, alone or in combination with T3, TSH suppression was achieved. We could show a robust uptake of (125)I-T3 for wild type (WT) MCT8, whereas no specific uptake could be detected for the mutant A150V. Subcellular localization of WT and mutant MCT8 revealed a strong cell surface expression for the WT MCT8, in contrast to A150V, which is mostly retained intracellularly with only weak cell surface expression. We could also demonstrate for the first time that WT MCT8 as well as the mutant are able to form multimers. CONCLUSION: Our findings open a wide field of possible interaction within the central nervous system and will help to understand the crucial role of MCT8 in early fetal brain development.- - - - - - - - - - ranking = 4keywords = cell (Clic here for more details about this article) |
4/4. The cognitive and behavioural phenotype of Roifman syndrome.BACKGROUND: Roifman syndrome (OMIM 300258) is a multi-system disorder with a physical phenotype that includes Beta-cell immunodeficiency, intra-uterine and postnatal growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy and characteristic facial dysmorphism. So far, six cases, all boys, have been reported in the literature. Roifman postulated that the syndrome may be due to a mutation in an X-linked gene or an autosomal gene giving rise to a sex-limited trait, but the definitive pathogenetic mechanism has still not been elucidated. Very little is known about the cognitive and behavioural phenotype of Roifman syndrome and no standardized measures of cognitive abilities have been reported. methods: We report the seventh case of a boy with Roifman syndrome and present the first systematic documentation of the cognitive and behavioural phenotype of an individual with the syndrome. RESULTS: In spite of having been reported as appearing intellectually 'able', formal evaluation showed very significant intellectual disability and neuropsychological impairment across cognitive domains. CONCLUSIONS: The findings suggest that Roifman syndrome may be an example of an X-linked mental retardation syndrome (XLMRS).- - - - - - - - - - ranking = 1keywords = cell (Clic here for more details about this article) |