Most cancer-associated BRCA1 mutations identified to date result in the premature translational termination of the protein, highlighting a crucial role for the C-terminal, BRCT repeat region in mediating BRCA1 tumor suppressor function. However, the molecular and genetic effects of missense mutations that map to the BRCT region remain largely unknown. Using a protease-based assay, we directly assessed the sensitivity of the folding of the BRCT domain to an extensive set of truncation and single amino acid substitutions derived from breast cancer screening programs. The protein can tolerate truncations of up to 8 amino acids, but further deletion results in drastic BRCT folding defects. This molecular phenotype can be correlated with an increased susceptibility to disease. A cross-validated computational assessment of the BRCT mutation data base suggests that as much as half of all BRCT missense mutations contribute to BRCA1 loss of function and disease through protein-destabilizing effects. The coupled use of proteolytic methods and computational predictive methods to detect mutant BRCA1 conformations at the protein level will augment the efficacy of current BRCA1 screening protocols, especially in the absence of clinical data that can be used to discriminate deleterious BRCT missense mutations from benign polymorphisms.Germline mutations within the breast and ovarian cancer susceptibility gene BRCA1 predispose carriers to early-onset breast and breast-ovarian cancers (1). Accumulating evidence points to a role for the BRCA1 protein product in the regulation of multiple nuclear functions including transcription, recombination, DNA repair, and checkpoint control (2-4). Tumor-associated mutations occur throughout the BRCA1 coding sequence, but cluster to sequences encoding the N-terminal RING finger domain and the two carboxy-terminal repeat BRCT 1 domains (5-7).The molecular details of how BRCA1 mutations contribute to the pathogenesis of cancer remain largely unknown. The functional significance of the BRCT region is highlighted by the high degree of sequence conservation within the BRCT regions of among mammalian, Xenopus, and avian BRCA1 homologues (8 -10). Several lines of evidence reveal the BRCT is required for tumor suppressor function. A nonsense mutation, which removes 11 C-terminal residues of the second, BRCT (Tyr 1853 3 stop), is associated with early-onset breast cancer (11). Two cancer-linked BRCT missense mutations (12) that destabilize the BRCT fold (13-15), A1708E and M1775R, ablate the double-strand break repair and transcription function of BRCA1 (16) and inhibit BRCT interactions with histone deacetylases (17), BACH1 (18), and the transcriptional co-repressor CtIP (19,20). Furthermore, mice with homozygous targeted mutations removing the C-terminal half of BRCA1 are viable but develop tumors, suggesting the missing BRCT and/or other domains are expendable for survival, but not for tumor suppression (21).Although all frameshift or nonsense mutations recorded in the Breast cancer Information Cor...

Our objective was to characterize the structural and metabolic changes of the corticospinal tract (CST) in ALS patients using combined diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI). Fourteen patients (male:female, 6:8; mean age, 54 years) and 14 controls (male:female, 8:6; mean age, 53 years) underwent imaging. Four regions of the CST were evaluated: precentral gyrus, corona radiata, posterior limb of the internal capsule, and cerebral peduncle. DTI and MRSI indices tested included fractional anisotropy (FA), apparent diffusion coefficient (ADC), and the ratio of N-acetylaspartate to choline (NAA/Cho) and creatine (NAA/Cr). In the precentral gyrus, NAA/Cho was reduced 18% (p<0.001), NAA/Cr was reduced 9% (p=0.01), and FA was reduced 3% (p=0.02). NAA/Cho and NAA/Cr were reduced in the corona radiata (p<0.001). Reduced NAA/Cho in the precentral gyrus correlated with shorter symptom duration (r=0.66, p=0.02) and faster disease progression (r=-0.65, p=0.008). Increased spasticity correlated with higher ADC in the precentral gyrus (R=0.52, p=0.005). In conclusion, both MRSI and DTI provided in vivo evidence of intracranial degeneration of the CST in ALS that was most prominent rostrally in the precentral gyrus.

BACKGROUND AND PURPOSE:Various lines of evidence implicate cerebral involvement beyond the motor cortex in ALS, including the cingulate gyrus and the thalamus. The purpose of this study was to assess neurodegeneration in these regions in vivo by using MRSI.

Purpose:To assess the quality of a navigator-gated, free breathing, steady-state free precession (SSFP) technique in comparison to a single breathhold for pulmonary artery imaging in normal volunteers. Materials and Methods:Sagittal sections of the left pulmonary arteries of 10 volunteers were obtained with a three-dimensional SSFP sequence using both a single breathhold of 30 seconds and a navigator-gated version of the same sequence. The images were compared and rated by a blinded cardiovascular radiologist for image quality, sharpness, and artifact.Results: On a scale ranging from -2 to 2, in which positive numbers denote that the navigator method was favorable compared to the single breathhold method, image quality was rated 0.7 Ϯ 1.4, sharpness 0.6 Ϯ 1.5, and artifact 0.1 Ϯ 1.4. Thus, there was no statistical difference between the two methods. Conclusion:The navigator-gated SSFP sequence is able to acquire images equal in quality to the breathhold sequence. This may be of clinical importance for pulmonary imaging in patients who are unable to sustain a long breathhold.

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