Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart

The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (Sspn(KO)) mice do not have heart defects, but Nkx2-5(+/−)/Sspn(KO) mutants have a higher incidence of muscular VSD than Nkx2-5(+/−) mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5(+/−)/Sspn(KO) mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

A porcine model of neurofibromatosis type 1 that mimics the human disease

Loss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients. Existing NF1 mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in NF1 (exon 42 deletion) orthologous to a mutation found in NF1 patients. NF1(+/ex42del) miniswine phenocopy the wide range of manifestations seen in NF1 patients, including cafe au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine NF1(+/ex42del) fibroblasts, as well as hyperactivation of Ras, as measured by increased expression of its downstream effectors, phosphorylated ERK1/2, SIAH, and the checkpoint regulators p53 and p21. Consistent with altered pain signaling in NF1, dysregulation of calcium and sodium channels was observed in dorsal root ganglia expressing mutant NF1. Thus, these NF1(+/ex42del) miniswine recapitulate the disease and provide a unique, much-needed tool to advance the study and treatment of NF1.Synodos for NF1 program at the Children's Tumor Foundation; Children's Tumor Foundation [2015-04-009A]; NIH [R01NS082283, 1R01NS098772, 1R01DA042852]; US Department of Defense Congressionally Directed Military Medical Research and Development Program [NF1000099]; NCI [P30-CA086862]; NIH shared instrumentation award [1S10OD02502501]; Pharmacological Sciences Training grant [2T32-GM0677954-14]; Children's Tumor FoundationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Measurement of the Mass of the Z-Boson and the Energy Calibration of Lep

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Electroweak parameters of the z0 resonance and the standard model

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