Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders.

Autor:	Ravindran E; Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, 10117, Germany.; Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, 13353, Germany.; Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Berlin 13353, Germany., Jühlen R; Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi, 6041, Belgium., Vieira-Vieira CH; Proteome Dynamics Lab, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany.; Humboldt-Universität zu Berlin, Faculty of Life Sciences, Berlin, 10099, Germany., Ha T; Genetics and Molecular Pathology Research Laboratory, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, 5000, Australia.; ACRF Cancer Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, 5000, SA, Australia., Salzberg Y; Azrieli Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel., Fichtman B; Azrieli Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel., Luise-Becker L; Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, 10117, Germany.; Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, 13353, Germany.; Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Berlin 13353, Germany., Martins N; Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi, 6041, Belgium., Picker-Minh S; Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, 10117, Germany.; Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, 13353, Germany.; Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Berlin 13353, Germany., Bessa P; Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, 10117, Germany., Arts P; Genetics and Molecular Pathology Research Laboratory, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, 5000, Australia., Jackson MR; Genetics and Molecular Pathology Research Laboratory, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, 5000, Australia.; Australian Genomic Health Alliance, Melbourne, VIC, 3052, Australia., Taranath A; Department of Medical imaging, South Australia Medical Imaging, Women's and Children's Hospital, North Adelaide, 5006, SA, Australia., Kamien B; Genetic Services of Western Australia, Perth, 6008, Australia., Barnett C; Australian Genomic Health Alliance, Melbourne, VIC, 3052, Australia.; Paediatric and Reproductive Genetics Unit, South Australian Clinical Genetics Service, Women's and Children's Hospital, North Adelaide, 5006, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, 5000, SA, Australia., Li N; Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China., Tarabykin V; Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, 10117, Germany.; Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, 634009, Russia., Stoltenburg-Didinger G; Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, 10117, Germany., Harel A; Azrieli Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel., Selbach M; Proteome Dynamics Lab, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany., Dickmanns A; Department of Molecular Structural Biology, Institute for Microbiology and Genetics (GZMB), Georg-August-University Göttingen, Göttingen, 37073, Germany., Fahrenkrog B; Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi, 6041, Belgium., Hu H; Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.; Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 , China., Scott H; Genetics and Molecular Pathology Research Laboratory, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, 5000, Australia.; ACRF Cancer Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, 5000, SA, Australia.; Australian Genomic Health Alliance, Melbourne, VIC, 3052, Australia.; School of Medicine, University of Adelaide, Adelaide, 5000, SA, Australia.; UniSA Clinical and Health Sciences, University of South Australia, Adelaide, 5000, Australia.; School of Biological Sciences, University of Adelaide, Adelaide, 5000, SA, Australia., Kaindl AM; Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, 10117, Germany.; Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, 13353, Germany.; Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Berlin 13353, Germany.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2021 Nov 01; Vol. 30 (22), pp. 2068-2081.
DOI:	10.1093/hmg/ddab160
Abstrakt:	Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS) include a heterogeneous group of autosomal recessive inherited diseases characterized by primary (congenital) microcephaly, the absence of visceral abnormalities, and a variable degree of cognitive impairment, short stature and facial dysmorphism. Recently, biallelic variants in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here, we report biallelic variants in NUP85 in two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS, thereby expanding the phenotypic spectrum of NUP85-linked diseases. Structural analysis predicts the identified NUP85 variants cause conformational changes that could have an effect on NPC architecture or on its interaction with other NUPs. We show that mutant NUP85 is, however, associated with a reduced number of NPCs but unaltered nucleocytoplasmic compartmentalization, abnormal mitotic spindle morphology, and decreased cell viability and proliferation in one patient's cells. Our results also indicate the link of common cellular mechanisms involved in MCPH-SCKS spectrum disorders and NUP85-associated diseases. In addition to the previous studies, our results broaden the phenotypic spectrum of NUP85-linked human disease and propose a role for NUP85 in nervous system development. (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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