Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only
Evans D.G.,St. Marys University |
Bowers N.,St. Marys University |
Burkitt-Wright E.,St. Marys University |
Miles E.,St. Marys University |
And 10 more authors.
EBioMedicine | Year: 2016
Background: The detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29. years by the National Institutes for Health (NIH) criteria which include ≥. 6 Café au Lait macules (CAL) as a defining criterion. The discovery of SPRED1 as a cause of Legius syndrome which is manifested by CAL, freckling and learning difficulties has introduced substantial heterogeneity to the NIH criteria. Methods: We have defined the sensitivity of comprehensive RNA analysis on blood of presumed NF1 patients meeting NIH criteria with at least one nonpigmentary criterion and determined the proportion of children with ≥. 6 CAL and no family history that has an NF1 or SPRED1 genetic variant. RNA analysis was carried out from 04/2009-12/2015 on 361 NF1 patients. Findings: A presumed causative NF1 mutation was found in 166/171 (97.08%-95% CI 94.56-99.6%) of familial cases and 182/190 (95.8%-95% CI 92.93-98.65%) sporadic de novo cases. Two of thirteen (15%) mutation negative individuals had dysembryoplastic neuroepithelial tumour (DNET) compared to 2/348 (0.6%) with an NF1 variant (p = 0.007). No SPRED1 variants were found in the thirteen individuals with no NF1 variant. Of seventy-one individuals with ≥. 6 CAL and no non-pigmentary criterion aged 0-20. years, 47 (66.2%) had an NF1 variant six (8.5%) a SPRED1 variant and 18 (25.3%) no disease causing variant. Using the 95.8% detection rate the likelihood of a child with ≥. 6 CAL having constitutional NF1 drops from 2/3 to 1/9 after negative RNA analysis. Interpretation: RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/. SPRED1 provides strong reassurance to children with ≥. 6 CAL that they are unlikely to have NF1. © 2016 The Authors.
Jakovljevic D.G.,Institute of Cellular Medicine |
Jakovljevic D.G.,Vitality |
Papakonstantinou L.,Institute of Cellular Medicine |
Blamire A.M.,Institute of Cellular Medicine |
And 6 more authors.
Circulation: Cardiovascular Imaging | Year: 2014
Background: Higher levels of physical activity are associated with reduced cardiovascular mortality but its effect on agerelated changes in cardiac structure and function is unknown. The present study defines the effect of daily physical activity on age-related changes in cardiac structure, function, metabolism, and performance in healthy women. Methods and Results: Sixty-three healthy women were grouped according to age (young, 20-30 years, n=21; middle, 40-50 years, n=22; and older, 65-81 years, n=20) and daily physical activity level (low active <7500 and high active >12 500 steps/d). Participants underwent cardiac MRI including tissue tagging and 31P spectroscopy and exercise testing with noninvasive central hemodynamic measurements. Aging was associated with increased concentric remodeling (P<0.01) and left ventricular torsion (P<0.01), and a decline in diastolic function (P<0.01), cardiac phosphocreatine:ATP ratio (P<0.01), peak exercise cardiac power output (P<0.01), and O2 consumption (P<0.01). Older high-active women demonstrated a phosphocreatine:ATP ratio and relative peak O2 consumption similar to young low-active women, and 23% and 26% higher than older low-active women (phosphocreatine:ATP ratio, 1.9±0.2 versus 1.4±0.1; P<0.05 and O2 consumption, 24.1±3.8 versus 17.8±2.0 mL/[kg·min]; P<0.01). In older women, physical activity had no effect on eccentricity ratio (0.9±0.2 versus 0.8±0.1 g/mL; P=0.19), E/A ratio (1.3±0.5 versus 1.4±0.5; P=0.66), torsion (7.6±1.7 versus 8.0°±2.1°; P=0.20), and peak cardiac power output (3.4±0.7 versus 3.4±0.8 W; P=0.91). Conclusions: A higher level of daily physical activity preserves cardiac metabolism and exercise capacity with aging but has limited effect on age-related changes in concentric remodeling, diastolic function, and cardiac performance. © 2014 American Heart Association, Inc.
Stanford S.M.,Institute for Genetic Medicine |
Stanford S.M.,La Jolla Institute for Allergy and Immunology |
Krishnamurthy D.,Institute for Genetic Medicine |
Krishnamurthy D.,University of Utah |
And 16 more authors.
Journal of Medicinal Chemistry | Year: 2011
The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, is a critical regulator of signaling in T cells and recently emerged as a candidate target for therapy of autoimmune diseases. Here, by library screening, we identified a series of noncompetitive inhibitors of LYP that showed activity in primary T cells. Kinetic analysis confirmed that binding of the compounds to the phosphatase is nonmutually exclusive with respect to a known bidentate competitive inhibitor. The mechanism of action of the lead inhibitor compound 4e was studied by a combination of hydrogen/deuterium-exchange mass spectrometry and molecular modeling. The results suggest that the inhibitor interacts critically with a hydrophobic patch located outside the active site of the phosphatase. Targeting of secondary allosteric sites is viewed as a promising yet unexplored approach to develop pharmacological inhibitors of protein tyrosine phosphatases. Our novel scaffold could be a starting point to attempt development of "nonactive site" anti-LYP pharmacological agents. © 2011 American Chemical Society.
Yang A.,Institute for Genetic Medicine |
Reeves R.H.,Institute for Genetic Medicine
Cancer Research | Year: 2011
Epidemiologic results tend to suggest that adults with Down syndrome have a reduced incidence of cancer, but some studies have reached the opposite conclusion. In this study, we offer direct biological evidence in support of the notion that Down syndrome reduces incidence of multiple types of cancer. Previous studies showed that introduction of the ApcMin mutation into the Ts65Dn mouse model of Down syndrome by interbreeding caused formation of intestinal adenomas at a significantly reduced incidence compared with control (euploid) animals that did not have trisomy. To a large degree, this reduction was determined to reflect an increased dosage of the Ets2 tumor repressor gene due to trisomy. Studies of tumor grafts using Ts65Dn suggested angiogenesis as a mechanism that mediated reduced tumor growth, metastasis, and mortality in individuals with Down syndrome. To confirm and extend these findings, we employed the complex cancer mouse model NPcis, which is heterozygous for the Trp53 and Nf1 genes and through LOH develops lymphomas, sarcomas, or carcinomas with 100% penetrance. In this aggressive model, trisomy did not prevent cancer, but it nevertheless extended host survival relative to euploid littermates. However, protection in this case was not attributable to either Ets2 dosage or to reduced angiogenesis. Together, our findings indicate that the genetic complexity underlying Down syndrome supports multiple mechanisms that contribute to reduced mortality from cancer. ©2011 AACR.