1/3. Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia.N-acetylglutamate synthase (NAGS) is a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate, an essential allosteric activator of carbamyl phosphate synthetase I, the first enzyme of the urea cycle. liver NAGS deficiency has previously been found in a small number of patients with hyperammonemia. The mouse and human NAGS genes have recently been cloned and expressed in our laboratory. We searched for mutations in the NAGS gene of two families with presumed NAGS deficiency. The exons and exon/intron boundaries of the NAGS gene were sequenced from genomic dna obtained from the parents of an infant from the Faroe islands who died in the neonatal period and from two Hispanic sisters who presented with acute neonatal hyperammonemia. Both parents of the first patient were found to be heterozygous for a null mutation in exon 4 (TGG-->TAG, Trp324Ter). Both sisters from the second family were homozygous for a single base deletion in exon 4 (1025delG) causing a frameshift and premature termination of translation. The finding of deleterious mutations in the NAGS gene confirms the genetic origin of NAGS deficiency. This disorder can now be diagnosed by dna testing allowing for carrier detection and prenatal diagnosis.- - - - - - - - - - ranking = 1keywords = cycle (Clic here for more details about this article) |
2/3. A homozygous frameshift mutation in the ESCO2 gene: evidence of intertissue and interindividual variation in Nmd efficiency.Roberts syndrome (RS) is a rare disorder characterized by tetraphocomelia and several other clinical features. Cells from RS patients exhibit characteristic premature separation of heterochromatic region of many chromosomes and abnormalities in cell cycle. Mutations in the ESCO2 gene have recently been identified in 20 RS families. We performed mutational analysis of the ESCO2 gene in two fetuses diagnosed with RS and their normal parents. In both fetuses, we identified homozygosity for the c. 745_746delGT mutation, while the non-consanguineous parents were both heterozygous for the same mutation. Considering the position of the mutation identified, we carried out qualitative and quantitative real-time ESCO2 cDNA analysis on rna isolated from CVS-stromal cells in one fetus, amniocytes in the second fetus, and lymphocytes from the heterozygous parents. The results of this analysis showed that despite the presence of a premature termination codon (PTC) 112 nucleotides upstream of the next exon3-exon4 junction, the mutant ESCO2 mRNA was present in both fetuses, albeit at low levels, indicating a partial resistance to nonsense mediated decay (NMD). Interestingly, when cells derived from the two fetuses were treated with an inhibitor of translation, they revealed the presence of tissue and individual variability in NMD efficiency, despite the identical mutational status. The existence of such a variation in the NMD efficiency could explain the broad intrafamilial and interfamilial variability in the clinical presentation of RS patients, and in other genetic diseases where nonsense mutations are responsible for most of the mutation load. Moreover, considering that a mutated full length mRNA was produced in both fetuses, we used Western blot analysis to demonstrate the absence of the ESCO2-truncated protein in cells derived from both fetuses and in a lymphoblastoid cell line derived from the parents.- - - - - - - - - - ranking = 1keywords = cycle (Clic here for more details about this article) |
3/3. Familial transmission of a duplication-deficiency x chromosome associated with partial turner syndrome.A rearranged x chromosome Xqter-->q13::Xp11.4-->qter was found in a mother and her two daughters, who were affected with short stature, cubitus valgus and hypothyroidism. The mother's menstrual cycles were normal until the age of premenopause. Similar previously reported cases are considered in an attempt to explain the possible origin of this X recombinant, fertility and clinical traits.- - - - - - - - - - ranking = 1keywords = cycle (Clic here for more details about this article) |