%0 Journal Article %J Am J Hum Genet %D 2023 %T Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage. %A Lecca, Mauro %A Pehlivan, Davut %A Suñer, Damià Heine %A Weiss, Karin %A Coste, Thibault %A Zweier, Markus %A Oktay, Yavuz %A Danial-Farran, Nada %A Rosti, Vittorio %A Bonasoni, Maria Paola %A Malara, Alessandro %A Contrò, Gianluca %A Zuntini, Roberta %A Pollazzon, Marzia %A Pascarella, Rosario %A Neri, Alberto %A Fusco, Carlo %A Marafi, Dana %A Mitani, Tadahiro %A Posey, Jennifer Ellen %A Bayramoglu, Sadik Etka %A Gezdirici, Alper %A Hernandez-Rodriguez, Jessica %A Cladera, Emilia Amengual %A Miravet, Elena %A Roldan-Busto, Jorge %A Ruiz, María Angeles %A Bauzá, Cristofol Vives %A Ben-Sira, Liat %A Sigaudy, Sabine %A Begemann, Anaïs %A Unger, Sheila %A Gungor, Serdal %A Hiz, Semra %A Sonmezler, Ece %A Zehavi, Yoav %A Jerdev, Michael %A Balduini, Alessandra %A Zuffardi, Orsetta %A Horvath, Rita %A Lochmüller, Hanns %A Rauch, Anita %A Garavelli, Livia %A Tournier-Lasserve, Elisabeth %A Spiegel, Ronen %A James R Lupski %A Errichiello, Edoardo %K Alleles %K Animals %K Brain Diseases %K Cell Adhesion Molecules %K Endothelial Cells %K Humans %K Intracranial Hemorrhages %K Mice %K Nervous System Malformations %K Neurodevelopmental Disorders %K Tight Junctions %X

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

%B Am J Hum Genet %V 110 %P 681-690 %8 2023 Apr 06 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/36996813?dopt=Abstract %R 10.1016/j.ajhg.2023.03.005 %0 Journal Article %J Nature %D 2014 %T Gibbon genome and the fast karyotype evolution of small apes. %A Carbone, Lucia %A Harris, R Alan %A Gnerre, Sante %A Veeramah, Krishna R %A Lorente-Galdos, Belen %A Huddleston, John %A Meyer, Thomas J %A Herrero, Javier %A Roos, Christian %A Aken, Bronwen %A Anaclerio, Fabio %A Archidiacono, Nicoletta %A Baker, Carl %A Barrell, Daniel %A Batzer, Mark A %A Beal, Kathryn %A Blancher, Antoine %A Bohrson, Craig L %A Brameier, Markus %A Campbell, Michael S %A Capozzi, Oronzo %A Casola, Claudio %A Chiatante, Giorgia %A Cree, Andrew %A Damert, Annette %A De Jong, Pieter J %A Dumas, Laura %A Fernandez-Callejo, Marcos %A Flicek, Paul %A Fuchs, Nina V %A Gut, Ivo %A Gut, Marta %A Hahn, Matthew W %A Hernandez-Rodriguez, Jessica %A Hillier, LaDeana W %A Hubley, Robert %A Ianc, Bianca %A Izsvák, Zsuzsanna %A Jablonski, Nina G %A Johnstone, Laurel M %A Karimpour-Fard, Anis %A Konkel, Miriam K %A Kostka, Dennis %A Lazar, Nathan H %A Lee, Sandra L %A Lewis, Lora R %A Liu, Yue %A Locke, Devin P %A Mallick, Swapan %A Mendez, Fernando L %A Muffato, Matthieu %A Nazareth, Lynne V %A Nevonen, Kimberly A %A O'Bleness, Majesta %A Ochis, Cornelia %A Odom, Duncan T %A Pollard, Katherine S %A Quilez, Javier %A Reich, David %A Rocchi, Mariano %A Schumann, Gerald G %A Searle, Stephen %A Sikela, James M %A Skollar, Gabriella %A Smit, Arian %A Sonmez, Kemal %A ten Hallers, Boudewijn %A Terhune, Elizabeth %A Thomas, Gregg W C %A Ullmer, Brygg %A Ventura, Mario %A Walker, Jerilyn A %A Wall, Jeffrey D %A Walter, Lutz %A Ward, Michelle C %A Wheelan, Sarah J %A Whelan, Christopher W %A White, Simon %A Wilhelm, Larry J %A Woerner, August E %A Yandell, Mark %A Zhu, Baoli %A Hammer, Michael F %A Marques-Bonet, Tomas %A Eichler, Evan E %A Fulton, Lucinda %A Fronick, Catrina %A Muzny, Donna M %A Warren, Wesley C %A Worley, Kim C %A Rogers, Jeffrey %A Wilson, Richard K %A Gibbs, Richard A %K Animals %K Evolution, Molecular %K Genome %K Hominidae %K Humans %K Hylobates %K Karyotype %K Molecular Sequence Data %K Phylogeny %K Retroelements %K Selection, Genetic %K Transcription Termination, Genetic %X

Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ∼5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.

%B Nature %V 513 %P 195-201 %8 2014 Sep 11 %G eng %N 7517 %1 https://www.ncbi.nlm.nih.gov/pubmed/25209798?dopt=Abstract %R 10.1038/nature13679