A novel TBX1 missense mutation in patients with syndromic congenital heart defects.

Congenital heart defects represent a characteristic part of several genetic syndromes associated with chromosomal abnormalities such as 22q11.2 deletion syndrome; many genes located in this locus, mainly TBX1, are candidate genes for congenital heart defects. In our cohort of 27 subjects with congenital heart defect, both karyotype analysis and Fluorescence in situ hybridization (FISH) were performed. The TBX1 gene was sequenced in patients lacking chromosomal abnormalities. FISH analysis showed a de novo 22q11.2 deletion in two patients. The screening of TBX1 coding sequence identified a novel missense mutation c.569C > A (p.P190Q) in six unrelated patients and detected two associated known single nucleotide polymorphisms; the c.664C > T (rs2301558) in three patients and the c.420T > C (p.Phe140 Phe) (rs41298814) in one patient. Bioinformatic tools show that the novel missense mutation c.569C > A could modify the function and the stability of the TBX1 protein. The c.569C > A mutation was not found in 50 healthy controls. Ours results suggest a deleterious role of the c.569C > A mutation and strengthen the hypothesis that this mutation might be responsible for the same phenotype spectrum as the 22q11.2 deletion syndrome.

Cytogenetic monitoring of hospital staff exposed to ionizing radiation: optimize protocol considering DNA repair genes variability.

PURPOSE: Chronic occupational exposure to ionizing radiation (IR) induces a wide spectrum of DNA damages. The aim of this study was to assess the frequencies of micronucleus (MN), sister chromatid exchanges (SCE) and to evaluate their association with XRCC1 399 Arg/Gln and XRCC3 241 Thr/Met polymorphisms in Hospital staff occupationally exposed to IR. MATERIALS AND METHODS: A questionnaire followed by a cytogenetic analysis was concluded for each subject in our study. The exposed subjects were classified into two groups based on duration of employment (Group I < 15 years; Group II ≥15years). The genotypes of all individuals (subjects and controls) were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: DNA damage frequencies were significantly greater in IR workers compared with controls (p < .05). However, no association arised between XRCC1 399 Arg/Gln and XRCC3 241 Thr/Met polymorphisms, on one hand, and the severity of DNA damages in the studied cohort of Tunisian population, on the other hand. CONCLUSION: Our data provide evidence for an obvious genotoxic effect associated with IR exposure and reinforce the high sensitivity of cytogenetic assays for biomonitoring of occupationally exposed populations. These results indicate that workers exposed to IR should have periodic monitoring, along their exposure. The variants, rs25487 and rs861539, of XRCC1 and XRCC3 genes have obvious functional effects. Paradoxically, these variants are not associated with the severity of damages, according to used assays, in the studied cohort of Tunisian population, unlike other studies.

Oxidative stress and glutathione S-transferase genetic polymorphisms in medical staff professionally exposed to ionizing radiation.

PURPOSE: Ionizing radiation (IR) is considered as a diagnostic and therapeutic tool in medicine. However, chronic occupational exposure of medical staff to IR may affect the antioxidant status and, as a result, DNA damage and cancers as well. The objective of our study was to evaluate the oxidative stress profile caused by IR in 29 Tunisian medical staff from radiology and radiotherapy departments, and to find an association between the GSTM1 null, GSTT1 null, and GSTP1 Ile105Val polymorphisms and oxidative stress biomarkers. MATERIALS AND METHODS: The oxidant biomarkers malondialdehyde (MDA) and advanced oxidation protein product (AOPP) and the activities of the antioxidant superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) enzymes were spectrophotometrically determined in erythrocytes hemolysates. The analysis of GSTT1 null, GSTM1 null, and GSTP1 Ile105Val polymorphisms was determined for each participant using PCR methods. RESULTS: A significant increase of white blood cell (WBC) numbers (p < .05) and a significant decrease by 11% of hemoglobin (Hb) (p < .01) were noted in the exposed subjects in our study. Moreover, we report a significant increase of MDA level and the activities of SOD and CAT enzymes of the IR-exposed group compared to controls (p < .001). Interestingly, a close association was noted between the genotypes GSTP1 low active, GSTT1 null, GSTM1 null, and both GSTT1/GSTM1 null and oxidative stress biomarkers, especially with MDA level, SOD, and CAT activities. CONCLUSIONS: Our findings indicate that the medical staff exposed to low IR levels were under risk of significant oxidative stress that was enhanced by their glutathione S-transferase (GST) polymorphisms.

Phenotypic variability in two infants sharing the same MECP2 mutation: evidence of chromosomal rearrangements and high sister-chromatid exchange levels in Rett syndrome.

Rett syndrome (RTT) whose major cause is the mutations in the X-linked MECP2 gene is a genetic disease that affects females. We screened two RTT patients using cytogenetic studies and in silico analysis as well as molecular analysis by the direct sequencing of MECP2. The cytogenetic results showed that although patient A was karyotypically normal, patient B showed chromosomal abnormalities, including chromosomal breakage in both chromosomes 2 and 5. In addition, chromosome 9 was detected on heteromorphic pattern (9ph+). A significant increase in sister-chromatid exchange (SCE) frequency was also observed in this patient. Although both patients were karyotypically different, they share the same MeCP2 mutation (p.P152R) which was predicted to be deleterious. To our knowledge, we describe the first association between MECP2 mutation, chromosomal abnormalities and high SCE frequency, which further validates the importance of the thorough chromosomal and molecular analyses that should be performed on the suspected RTT cases.