ABSTRACT: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported. Identification of pathogenic mutation is important for diagnostic confirmation of the disease, however genetic counselling and testing of relatives at risk is critical in mutation carriers.
Mutation analysis of the NOTCH3 gene was performed through direct sequencing in 140 patients with clinical suspicion of CADASIL. Patients underwent genetic counselling pre and post testing. The 2-23 exons containing all EGF-like domains were screened.
14 familial forms of the disease have been identified with 14 different causative mutations in exons 2, 3, 4, 5, 7, 10, 14, 19, 20 and 22 of the NOTCH3 gene; no pathogenetic mutations have been identified in exons 6 and 8; several genetic variations both in coding as well as in intronic regions were identified too.
Our data confirm the importance of screening the whole EGF-like domains region of NOTCH3 gene for the molecular diagnosis of CADASIL among the Italian population too. Moreover genetic variants different from loss or gain of a cysteine residue are identified and presented.
Journal of the neurological sciences 05/2011; 307(1-2):144-8. · 2.32 Impact Factor
Human Genetics 04/2010; 127(4):468. · 5.07 Impact Factor
ABSTRACT: XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients.
We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy.
The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P=0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found.
This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non-platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.
Clinical Cancer Research 06/2007; 13(10):2876-81. · 7.74 Impact Factor
ABSTRACT: Mutations of the AGXT gene encoding the alanine:glyoxylate aminotransferase liver enzyme (AGT) cause primary hyperoxaluria type 1 (PH1). Here we report a molecular modeling study of selected missense AGXT mutations: the common Gly170Arg and the recently described Gly47Arg and Ser81Leu variants, predicted to be pathogenic using standard criteria.
Taking advantage of the refined 3D structure of AGT, we computed the dimerization energy of the wild-type and mutated proteins.
Molecular modeling predicted that Gly47Arg affects dimerization with a similar effect to that shown previously for Gly170Arg through classical biochemical approaches. In contrast, no effect on dimerization was predicted for Ser81Leu. Therefore, this probably demonstrates pathogenic properties via a different mechanism, similar to that described for the adjacent Gly82Glu mutation that affects pyridoxine binding.
This study shows that the molecular modeling approach can contribute to evaluating the pathogenicity of some missense variants that affect dimerization. However, in silico studies--aimed to assess the relationship between structural change and biological effects--require the integrated use of more than 1 tool.
Journal of nephrology 23(6):667-76. · 1.65 Impact Factor