Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly
Nucleoporin (NUP) 85 is a member of the Y-complex of nuclear pore complex (NPC) that is key for nucleocytoplasmic transport function, regulation of mitosis, transcription, and chromatin organization. Mutations in various nucleoporin genes have been linked to several human diseases. Among them, NUP85...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2023.1124886/full |
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| author | Ethiraj Ravindran Ethiraj Ravindran Ethiraj Ravindran Gaetan Lesca Gaetan Lesca Louis Januel Linus Goldgruber Achim Dickmanns Henri Margot Angela M. Kaindl Angela M. Kaindl Angela M. Kaindl |
| author_facet | Ethiraj Ravindran Ethiraj Ravindran Ethiraj Ravindran Gaetan Lesca Gaetan Lesca Louis Januel Linus Goldgruber Achim Dickmanns Henri Margot Angela M. Kaindl Angela M. Kaindl Angela M. Kaindl |
| author_sort | Ethiraj Ravindran |
| collection | DOAJ |
| description | Nucleoporin (NUP) 85 is a member of the Y-complex of nuclear pore complex (NPC) that is key for nucleocytoplasmic transport function, regulation of mitosis, transcription, and chromatin organization. Mutations in various nucleoporin genes have been linked to several human diseases. Among them, NUP85 was linked to childhood-onset steroid-resistant nephrotic syndrome (SRNS) in four affected individuals with intellectual disability but no microcephaly. Recently, we broaden the phenotype spectrum of NUP85-associated disease by reporting NUP85 variants in two unrelated individuals with primary autosomal recessive microcephaly (MCPH) and Seckel syndrome (SCKS) spectrum disorders (MCPH-SCKS) without SRNS. In this study, we report compound heterozygous NUP85 variants in an index patient with only MCPH phenotype, but neither Seckel syndrome nor SRNS was reported. We showed that the identified missense variants cause reduced cell viability of patient-derived fibroblasts. Structural simulation analysis of double variants is predicted to alter the structure of NUP85 and its interactions with neighboring NUPs. Our study thereby further expands the phenotypic spectrum of NUP85-associated human disorder and emphasizes the crucial role of NUP85 in the brain development and function. |
| first_indexed | 2024-04-10T16:25:15Z |
| format | Article |
| id | doaj.art-ed1e140840424257b23b4291c8670577 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-04-10T16:25:15Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-ed1e140840424257b23b4291c86705772023-02-09T07:20:56ZengFrontiers Media S.A.Frontiers in Neurology1664-22952023-02-011410.3389/fneur.2023.11248861124886Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephalyEthiraj Ravindran0Ethiraj Ravindran1Ethiraj Ravindran2Gaetan Lesca3Gaetan Lesca4Louis Januel5Linus Goldgruber6Achim Dickmanns7Henri Margot8Angela M. Kaindl9Angela M. Kaindl10Angela M. Kaindl11Institute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Pediatric Neurology, Charité – Universitätsmedizin Berlin, Berlin, GermanyCenter for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Genetics, Hospices Civils de Lyon, Groupe Hospitalier Est, Bron, FranceInstitut NeuroMyoGene PNMG, CNRS UMR5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, FranceDepartment of Genetics, Hospices Civils de Lyon, Groupe Hospitalier Est, Bron, FranceDepartment of Biomedical Engineering, Veterinärmedizinische Universität (Vetmeduni), Vienna, AustriaDepartment of Molecular Structural Biology, Institute for Microbiology and Genetics (GZMB), Georg-August-University Göttingen, Göttingen, GermanyDepartment of Medical Genetics, University of Bordeaux, MRGM INSERM U1211, CHU de Bordeaux, Bordeaux, FranceInstitute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Pediatric Neurology, Charité – Universitätsmedizin Berlin, Berlin, GermanyCenter for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Charité – Universitätsmedizin Berlin, Berlin, GermanyNucleoporin (NUP) 85 is a member of the Y-complex of nuclear pore complex (NPC) that is key for nucleocytoplasmic transport function, regulation of mitosis, transcription, and chromatin organization. Mutations in various nucleoporin genes have been linked to several human diseases. Among them, NUP85 was linked to childhood-onset steroid-resistant nephrotic syndrome (SRNS) in four affected individuals with intellectual disability but no microcephaly. Recently, we broaden the phenotype spectrum of NUP85-associated disease by reporting NUP85 variants in two unrelated individuals with primary autosomal recessive microcephaly (MCPH) and Seckel syndrome (SCKS) spectrum disorders (MCPH-SCKS) without SRNS. In this study, we report compound heterozygous NUP85 variants in an index patient with only MCPH phenotype, but neither Seckel syndrome nor SRNS was reported. We showed that the identified missense variants cause reduced cell viability of patient-derived fibroblasts. Structural simulation analysis of double variants is predicted to alter the structure of NUP85 and its interactions with neighboring NUPs. Our study thereby further expands the phenotypic spectrum of NUP85-associated human disorder and emphasizes the crucial role of NUP85 in the brain development and function.https://www.frontiersin.org/articles/10.3389/fneur.2023.1124886/fullNUP85microcephalybrain developmentspeech disorderMCPH-SCKS |
| spellingShingle | Ethiraj Ravindran Ethiraj Ravindran Ethiraj Ravindran Gaetan Lesca Gaetan Lesca Louis Januel Linus Goldgruber Achim Dickmanns Henri Margot Angela M. Kaindl Angela M. Kaindl Angela M. Kaindl Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly Frontiers in Neurology NUP85 microcephaly brain development speech disorder MCPH-SCKS |
| title | Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly |
| title_full | Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly |
| title_fullStr | Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly |
| title_full_unstemmed | Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly |
| title_short | Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly |
| title_sort | case report compound heterozygous nup85 variants cause autosomal recessive primary microcephaly |
| topic | NUP85 microcephaly brain development speech disorder MCPH-SCKS |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2023.1124886/full |
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