Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence

Edith Bonnin; Pauline Cabochette; Alessandro Filosa; Ramona Jühlen; Shoko Komatsuzaki; Mohammed Hezwani; Achim Dickmanns; Valérie Martinelli; Marjorie Vermeersch; Lynn Supply; Nuno Martins; Laurence Pirenne; Gianina Ravenscroft; Marcus Lombard; Sarah Port; Christiane Spillner; Sandra Janssens; Ellen Roets; Jo Van Dorpe; Martin Lammens; Ralph H Kehlenbach; Ralf Ficner; Nigel G Laing; Katrin Hoffmann; Benoit Vanhollebeke; Birthe Fahrenkrog

doi:10.1371/journal.pgen.1007845

Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence

PLoS Genet. 2018 Dec 13;14(12):e1007845. doi: 10.1371/journal.pgen.1007845. eCollection 2018 Dec.

Authors

Edith Bonnin^{1

2}, Pauline Cabochette², Alessandro Filosa³, Ramona Jühlen¹, Shoko Komatsuzaki⁴, Mohammed Hezwani¹, Achim Dickmanns⁵, Valérie Martinelli¹, Marjorie Vermeersch⁶, Lynn Supply⁷, Nuno Martins¹, Laurence Pirenne¹, Gianina Ravenscroft⁸, Marcus Lombard⁸, Sarah Port⁹, Christiane Spillner⁹, Sandra Janssens¹⁰, Ellen Roets¹¹, Jo Van Dorpe⁷, Martin Lammens¹², Ralph H Kehlenbach⁹, Ralf Ficner⁵, Nigel G Laing⁸, Katrin Hoffmann⁴, Benoit Vanhollebeke^{2

13}, Birthe Fahrenkrog¹

Affiliations

¹ Institute of Molecular Biology and Medicine, Laboratory Biology of the Cell Nucleus, Université Libre de Bruxelles (ULB), Gosselies, Belgium.
² Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Gosselies, Belgium.
³ Max Delbrück Center for Molecular Medicine, Berlin, Germany.
⁴ Institute of Human Genetics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
⁵ Department of Molecular Structural Biology, Institute for Microbiology and Genetics, GZMB, Georg-August-University Göttingen, Göttingen, Germany.
⁶ Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles, Charleroi, Belgium.
⁷ Department of Pathology, Ghent University, Ghent University Hospital, Ghent, Belgium.
⁸ Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
⁹ Department of Molecular Biology, Faculty of Medicine, Georg-August-University of Göttingen, Göttingen, Germany.
¹⁰ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
¹¹ Department of Obstetrics and Gynecology, Prenatal Diagnosis Centre, Ghent University Hospital, Ghent, Belgium.
¹² Department of Pathology, Antwerp University Hospital, Egdem, Belgium.
¹³ Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Belgium.

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

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Amino Acid Sequence
Animals
Animals, Genetically Modified
Arthrogryposis / embryology
Arthrogryposis / genetics*
Arthrogryposis / physiopathology
Consanguinity
Disease Models, Animal
Female
Genes, Lethal*
Humans
Male
Mice
Models, Molecular
Muscle Proteins / metabolism
Mutation*
Neuromuscular Junction / physiopathology
Nuclear Pore Complex Proteins / chemistry
Nuclear Pore Complex Proteins / deficiency
Nuclear Pore Complex Proteins / genetics*
Pedigree
Pregnancy
Protein Conformation
Receptors, Nicotinic / metabolism
Sequence Homology, Amino Acid
Zebrafish / abnormalities
Zebrafish / genetics
Zebrafish / physiology
Zebrafish Proteins / deficiency
Zebrafish Proteins / genetics

Substances

Muscle Proteins
NUP88 protein, human
Nuclear Pore Complex Proteins
Receptors, Nicotinic
Zebrafish Proteins
peripheral membrane protein 43K

Supplementary concepts

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.