RT Journal Article SR Electronic T1 Mutations in nucleoporin NUP88 cause lethal neuromuscular disorder JF bioRxiv FD Cold Spring Harbor Laboratory SP 347179 DO 10.1101/347179 A1 Edith Bonnin A1 Pauline Cabochette A1 Alessandro Filosa A1 Ramona Jühlen A1 Shoko Komatsuzaki A1 Mohammed Hezwani A1 Achim Dickmanns A1 Valérie Martinelli A1 Marjorie Vermeersch A1 Lynn Supply A1 Nuno Martins A1 Laurence Pirenne A1 Gianina Ravenscroft A1 Marcus Lombard A1 Sarah Port A1 Christiane Spillner A1 Sandra Janssens A1 Ellen Roets A1 Jo Van Dorpe A1 Martin Lammens A1 Ralph H. Kehlenbach A1 Ralf Ficner A1 Nigel Laing A1 Katrin Hoffmann A1 Benoit Vanhollebeke A1 Birthe Fahrenkrog YR 2018 UL http://biorxiv.org/content/early/2018/08/14/347179.abstract AB Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, are of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are only rescued by expressing wild-type nup88 and not the disease-linked mutant forms of nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.