4.5 Article

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

Journal

HUMAN MOLECULAR GENETICS
Volume 30, Issue 22, Pages 2068-2081

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab160

Keywords

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Funding

  1. German Research Foundation [SFB665, SFB1315, FOR3004]
  2. Sonnenfeld Stiftung
  3. Berlin Institute of Health (BIH) [CRG1]
  4. Charite
  5. Israel Science Foundation [985/15]
  6. National Health and Medical Research Council (NHMRC) [APP1123341]
  7. Australian Genomic Health Alliance NHMRC Targeted Call for Research into Preparing Australia for the Genomics Revolution in Healthcare [GNT1113531]
  8. Beat Cancer Principal Research Fellowship
  9. Medical Research Future Fund [GHFM76777]
  10. Major Medical Collaboration and Innovation Program of Guangzhou Science Technology and Innovation Commission [201604020020]
  11. National Natural Science Foundation of China [81671067, 81974163, 81701451]
  12. Russian Science Foundation [21-65-00017]
  13. National Human Genome Research Institute
  14. National Eye Institute
  15. National Heart, Lung and Blood Institute [UM1 HG008900]
  16. Russian Science Foundation [21-65-00017] Funding Source: Russian Science Foundation

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Biallelic variants in the NUP85 gene have been found to cause MCPH-SCKS spectrum disorders, expanding the phenotypic spectrum of NUP85-related diseases and suggesting a role for NUP85 in nervous system development.
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.

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