Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly

Ethiraj Ravindran; Gaetan Lesca; Louis Januel; Linus Goldgruber; Achim Dickmanns; Henri Margot; Angela M Kaindl

doi:10.3389/fneur.2023.1124886

Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly

Front Neurol. 2023 Feb 9:14:1124886. doi: 10.3389/fneur.2023.1124886. eCollection 2023.

Authors

Ethiraj Ravindran^{1

2

3}, Gaetan Lesca^{4

5}, Louis Januel⁴, Linus Goldgruber⁶, Achim Dickmanns⁷, Henri Margot⁸, Angela M Kaindl^{1

2

3}

Affiliations

¹ Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
² Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
³ Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁴ Department of Genetics, Hospices Civils de Lyon, Groupe Hospitalier Est, Bron, France.
⁵ Institut NeuroMyoGene PNMG, CNRS UMR5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France.
⁶ Department of Biomedical Engineering, Veterinärmedizinische Universität (Vetmeduni), Vienna, Austria.
⁷ Department of Molecular Structural Biology, Institute for Microbiology and Genetics (GZMB), Georg-August-University Göttingen, Göttingen, Germany.
⁸ Department of Medical Genetics, University of Bordeaux, MRGM INSERM U1211, CHU de Bordeaux, Bordeaux, France.

Abstract

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.

Keywords: MCPH-SCKS; NUP85; brain development; microcephaly; speech disorder.

Publication types

Case Reports

Grants and funding

This work was supported by the Einstein Stiftung Fellowship through the Günter Endres Fond (AK), the German Research Foundation (DFG, SFB1315, FOR3004, AK), and the Charité (AK, ER). This work was supported by the Institut national de la santé et de la recherche médicale (Inserm), sponsor of the DEFIDIAG study (NCT04154891). The DEFIDIAG study was funded by The French Ministry of Health in the framework of the French initiative for genomic medicine (Plan France Médecine Génomique 2025; PFMG 2025; https://pfmg2025.aviesan.fr/). The DEIFIDIAG study was supported by government funding from the Agence Nationale de la Recherche under the “Investissements d'avenir” program (ANR-10-IAHU-01).