@article {914, title = {Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.}, journal = {Nat Med}, volume = {26}, year = {2020}, month = {2020 11}, pages = {1754-1765}, abstract = {

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17\% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22\% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

}, keywords = {Brain, Cerebral Ventricles, Exome, Female, Genetic Predisposition to Disease, Humans, Hydrocephalus, Male, Mutation, Neural Stem Cells, Neurogenesis, Neuroglia, Transcription Factors, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Whole Exome Sequencing}, issn = {1546-170X}, doi = {10.1038/s41591-020-1090-2}, author = {Jin, Sheng Chih and Dong, Weilai and Kundishora, Adam J and Panchagnula, Shreyas and Moreno-De-Luca, Andres and Furey, Charuta G and Allocco, August A and Walker, Rebecca L and Nelson-Williams, Carol and Smith, Hannah and Dunbar, Ashley and Conine, Sierra and Lu, Qiongshi and Zeng, Xue and Sierant, Michael C and Knight, James R and Sullivan, William and Duy, Phan Q and DeSpenza, Tyrone and Reeves, Benjamin C and Karimy, Jason K and Marlier, Arnaud and Castaldi, Christopher and Tikhonova, Irina R and Li, Boyang and Pe{\~n}a, Helena Perez and Broach, James R and Kabachelor, Edith M and Ssenyonga, Peter and Hehnly, Christine and Ge, Li and Keren, Boris and Timberlake, Andrew T and Goto, June and Mangano, Francesco T and Johnston, James M and Butler, William E and Warf, Benjamin C and Smith, Edward R and Schiff, Steven J and Limbrick, David D and Heuer, Gregory and Jackson, Eric M and Iskandar, Bermans J and Mane, Shrikant and Haider, Shozeb and Guclu, Bulent and Bayri, Yasar and Sahin, Yener and Duncan, Charles C and Apuzzo, Michael L J and DiLuna, Michael L and Hoffman, Ellen J and {\v S}estan, Nenad and Ment, Laura R and Alper, Seth L and Bilguvar, Kaya and Geschwind, Daniel H and G{\"u}nel, Murat and Lifton, Richard P and Kahle, Kristopher T} } @article {802, title = {New drugs on the horizon for cerebral edema: what{\textquoteright}s in the clinical development pipeline?}, journal = {Expert Opin Investig Drugs}, volume = {29}, year = {2020}, month = {2020 Oct}, pages = {1099-1105}, abstract = {

INTRODUCTION: Research has advanced our understanding of the molecular and cellular mechanisms of cerebral edema and has propelled the development of novel antiedema therapeutics. Current evidence supports aberrant neuro-glial ion transport as a central mechanism that underlies pathological fluid accumulation after central nervous system injury.

AREAS COVERED: Novel agents in clinical development show potential in altering the natural history and treatment of cerebral edema. Using the PubMed and Google Scholar databases, we review recent advances in our understanding of cerebral edema and describe agents under active investigation, their mechanism, and their application in recent and ongoing clinical trials.

EXPERT OPINION: Pharmacotherapies that target molecular mechanisms underlying the compensatory post-injury response of ion channels and transporters that lead to pathological alteration of osmotic gradients are the most promising therapeutic strategies. Repurposing of drugs such as glyburide that inhibit the aberrant upregulation of ion channels such as SUR1-TRPM4, and novel agents, such as ZT-1a, which reestablish physiological regulation of ion channels such as NKCC1/KCC, could be useful adjuvants to prevent and even reverse fluid accumulation in the brain parenchyma.

}, keywords = {Animals, Brain Edema, Drug Development, Drug Repositioning, Drugs, Investigational, Humans, Molecular Targeted Therapy}, issn = {1744-7658}, doi = {10.1080/13543784.2020.1813715}, author = {Robert, Stephanie M and Reeves, Benjamin C and Alper, Seth L and Zhang, Jinwei and Kahle, Kristopher T} } @article {386, title = {De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 08 29}, pages = {E7341-E7347}, abstract = {

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95\% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, = 2.4 {\texttimes} 10). had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10\% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near increased the penetrance of mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

}, keywords = {Adult, Animals, Bone Morphogenetic Proteins, Child, Child, Preschool, Cranial Sutures, Craniosynostoses, Exome, Female, Humans, Male, MAP Kinase Signaling System, Mutation, Osteogenesis, Penetrance, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction, Smad6 Protein, Whole Exome Sequencing}, issn = {1091-6490}, doi = {10.1073/pnas.1709255114}, author = {Timberlake, Andrew T and Furey, Charuta G and Choi, Jungmin and Nelson-Williams, Carol and Loring, Erin and Galm, Amy and Kahle, Kristopher T and Steinbacher, Derek M and Larysz, Dawid and Persing, John A and Lifton, Richard P} }