Abstract
Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, is 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 rescued by expressing wild-type Nup88 but 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.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Amino Acid Sequence
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Animals
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Animals, Genetically Modified
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Arthrogryposis / embryology
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Arthrogryposis / genetics*
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Arthrogryposis / physiopathology
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Consanguinity
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Disease Models, Animal
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Female
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Genes, Lethal*
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Humans
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Male
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Mice
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Models, Molecular
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Muscle Proteins / metabolism
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Mutation*
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Neuromuscular Junction / physiopathology
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Nuclear Pore Complex Proteins / chemistry
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Nuclear Pore Complex Proteins / deficiency
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Nuclear Pore Complex Proteins / genetics*
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Pedigree
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Pregnancy
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Protein Conformation
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Receptors, Nicotinic / metabolism
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Sequence Homology, Amino Acid
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Zebrafish / abnormalities
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Zebrafish / genetics
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Zebrafish / physiology
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Zebrafish Proteins / deficiency
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Zebrafish Proteins / genetics
Substances
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Muscle Proteins
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NUP88 protein, human
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Nuclear Pore Complex Proteins
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Receptors, Nicotinic
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Zebrafish Proteins
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peripheral membrane protein 43K
Supplementary concepts
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Pena Shokeir syndrome, type 1
Grants and funding
This work was supported by grants from the Fédération Wallonie-Bruxelles (ARC 4.110.F.000092F), the Fonds Brachet and the Fonds Van Buuren to BF. and by a fellowship of Fonds Hoguet and Fonds Brachet to EB. Work in the B.V. laboratory is supported by the Fonds De La Recherche Scientifique (FNRS) (MIS F.4543.15), an ARC grant, the Fondation ULB, the Queen Elisabeth Medical Foundation for Neurosciences (Q.E.M.F.,) and the Fonds de la Recherche Scientifique - FNRS for the FRFS-WELBIO (CR-2017S-05). P.C. received a Postdoctoral fellowship from the FNRS. GR is supported by an Australian National Health and Medical Research Council (NHMRC) Career Development Fellowship (APP1122952), NGL by NHMRC Principal Research Fellowship (APP11117510). This work was funded by a NHMRC Project Grant (APP1080587) and the AFM (15734). S.P and R.H.K were supported by a grant from the DFG (SFB860). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.