@article {1009, title = {GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 Jul 05}, abstract = {

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

}, issn = {1540-9538}, doi = {10.1084/jem.20201745}, author = {Drzewiecki, Kaela and Choi, Jungmin and Brancale, Joseph and Leney-Greene, Michael A and Sari, Sinan and Dalgi{\c c}, Buket and {\"U}nl{\"u}soy Aksu, Aysel and Evirgen {\c S}ahin, G{\"u}lseren and Ozen, Ahmet and Baris, Safa and Karakoc-Aydiner, Elif and Jain, Dhanpat and Kleiner, David and Schmalz, Michael and Radhakrishnan, Kadakkal and Zhang, Junhui and Hoebe, Kasper and Su, Helen C and Pereira, Jo{\~a}o P and Lenardo, Michael J and Lifton, Richard P and Vilarinho, S{\'\i}lvia} } @article {794, title = {Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {2020 10}, pages = {1046-1056}, abstract = {

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14\% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

}, keywords = {Animals, beta Catenin, Cerebral Palsy, Cyclin D, Cytoskeleton, Drosophila, Exome, Extracellular Matrix, F-Box Proteins, Female, Focal Adhesions, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Mutation, Neurites, rhoB GTP-Binding Protein, Risk Factors, Sequence Analysis, DNA, Signal Transduction, Tubulin, Tumor Suppressor Proteins, Whole Exome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-020-0695-1}, author = {Jin, Sheng Chih and Lewis, Sara A and Bakhtiari, Somayeh and Zeng, Xue and Sierant, Michael C and Shetty, Sheetal and Nordlie, Sandra M and Elie, Aureliane and Corbett, Mark A and Norton, Bethany Y and van Eyk, Clare L and Haider, Shozeb and Guida, Brandon S and Magee, Helen and Liu, James and Pastore, Stephen and Vincent, John B and Brunstrom-Hernandez, Janice and Papavasileiou, Antigone and Fahey, Michael C and Berry, Jesia G and Harper, Kelly and Zhou, Chongchen and Zhang, Junhui and Li, Boyang and Zhao, Hongyu and Heim, Jennifer and Webber, Dani L and Frank, MAHlia S B and Xia, Lei and Xu, Yiran and Zhu, Dengna and Zhang, Bohao and Sheth, Amar H and Knight, James R and Castaldi, Christopher and Tikhonova, Irina R and L{\'o}pez-Gir{\'a}ldez, Francesc and Keren, Boris and Whalen, Sandra and Buratti, Julien and Doummar, Diane and Cho, Megan and Retterer, Kyle and Millan, Francisca and Wang, Yangong and Waugh, Jeff L and Rodan, Lance and Cohen, Julie S and Fatemi, Ali and Lin, Angela E and Phillips, John P and Feyma, Timothy and MacLennan, Suzanna C and Vaughan, Spencer and Crompton, Kylie E and Reid, Susan M and Reddihough, Dinah S and Shang, Qing and Gao, Chao and Novak, Iona and Badawi, Nadia and Wilson, Yana A and McIntyre, Sarah J and Mane, Shrikant M and Wang, Xiaoyang and Amor, David J and Zarnescu, Daniela C and Lu, Qiongshi and Xing, Qinghe and Zhu, Changlian and Bilguvar, Kaya and Padilla-Lopez, Sergio and Lifton, Richard P and Gecz, Jozef and MacLennan, Alastair H and Kruer, Michael C} } @article {426, title = {Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Nov}, pages = {1593-1601}, abstract = {

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8\%, including a recessive founder mutation in GDF1 accounting for \~{}5\% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for \~{}11\% of Shone complex, and dominant FLT4 mutations accounting for 2.3\% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8\% of cases, including \~{}3\% of isolated CHD patients and \~{}28\% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70\% probability of being disease related. DNMs in \~{}440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

}, keywords = {Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3}, issn = {1546-1718}, doi = {10.1038/ng.3970}, author = {Jin, Sheng Chih and Homsy, Jason and Zaidi, Samir and Lu, Qiongshi and Morton, Sarah and DePalma, Steven R and Zeng, Xue and Qi, Hongjian and Chang, Weni and Sierant, Michael C and Hung, Wei-Chien and Haider, Shozeb and Zhang, Junhui and Knight, James and Bjornson, Robert D and Castaldi, Christopher and Tikhonoa, Irina R and Bilguvar, Kaya and Mane, Shrikant M and Sanders, Stephan J and Mital, Seema and Russell, Mark W and Gaynor, J William and Deanfield, John and Giardini, Alessandro and Porter, George A and Srivastava, Deepak and Lo, Cecelia W and Shen, Yufeng and Watkins, W Scott and Yandell, Mark and Yost, H Joseph and Tristani-Firouzi, Martin and Newburger, Jane W and Roberts, Amy E and Kim, Richard and Zhao, Hongyu and Kaltman, Jonathan R and Goldmuntz, Elizabeth and Chung, Wendy K and Seidman, Jonathan G and Gelb, Bruce D and Seidman, Christine E and Lifton, Richard P and Brueckner, Martina} }